NCBI Conserved Domain Search

calmodulin; Provisional

Pssm-ID: 185504 [Multi-domain] Cd Length: 149 Bit Score: 144.13 E-value: 5.09e-45

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   2 IAEFKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMVRQMKEdakGKSEEEL 81
Cdd:PTZ00184  10 IAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLMARKMKD---TDSEEEI 86

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  82 AECFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMM 141
Cdd:PTZ00184  87 KEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMM 146

centrin; Provisional

Pssm-ID: 185503 [Multi-domain] Cd Length: 158 Bit Score: 105.93 E-value: 5.54e-30

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   2 IAEFKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMVRQMkedAKGKSEEEL 81
Cdd:PTZ00183  16 KKEIREAFDLFDTDGSGTIDPKELKVAMRSLGFEPKKEEIKQMIADVDKDGSGKIDFEEFLDIMTKKL---GERDPREEI 92

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  82 AECFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMM 141
Cdd:PTZ00183  93 LKAFRLFDDDKTGKISLKNLKRVAKELGETITDEELQEMIDEADRNGDGEISEEEFYRIM 152

Ca2+-binding protein, EF-hand superfamily [Signal transduction mechanisms];

Pssm-ID: 444056 [Multi-domain] Cd Length: 137 Bit Score: 80.61 E-value: 2.47e-20

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   5 FKAAFDMFDADGGGDISVKELGTVMRMLgqtptkeeLDAIIEEVDEDGSGTIDFEEFLVMMVRQMKEDAkgksEEELAEC 84
Cdd:COG5126    7 LDRRFDLLDADGDGVLERDDFEALFRRL--------WATLFSEADTDGDGRISREEFVAGMESLFEATV----EPFARAA 74

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 768018237  85 FRIFDRNADGYIDPEELAEIFRASGehVTDEEIESLMKDGDKNNDGRIDFDEFLKMMEG 143
Cdd:COG5126   75 FDLLDTDGDGKISADEFRRLLTALG--VSEEEADELFARLDTDGDGKISFEEFVAAVRD 131

EF-hand, calcium binding motif; A diverse superfamily of calcium sensors and calcium signal modulators; most examples in this alignment model have 2 active canonical EF hands. Ca2+ binding induces a conformational change in the EF-hand motif, leading to the activation or inactivation of target proteins. EF-hands tend to occur in pairs or higher copy numbers.

Pssm-ID: 238008 [Multi-domain] Cd Length: 63 Bit Score: 72.58 E-value: 5.56e-18

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 768018237  80 ELAECFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMM 141
Cdd:cd00051    1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELM 62

Penta-EF hand, calcium binding motifs, found in Group I PEF proteins; The family corresponds to Group I PEF proteins that have been found not only in higher animals but also in lower animals, plants, fungi and protists. Group I PEF proteins include apoptosis-linked gene 2 protein (ALG-2), peflin and similar proteins. ALG-2, also termed programmed cell death protein 6 (PDCD6), is a widely expressed calcium-binding modulator protein associated with cell proliferation and death, as well as cell survival. It forms a homodimer in the cell or a heterodimer with its closest paralog peflin. Among the PEF proteins, ALG-2 can bind three Ca2+ ions through its EF1, EF3, and EF5 hands, where it is unique in that its EF5 hand binds Ca2+ ion in a canonical coordination. Peflin is a ubiquitously expressed 30-kD PEF protein containing five EF-hand motifs in its C-terminal domain and a longer N-terminal hydrophobic domain (NHB domain) than any other member of the PEF family. The NHB domain harbors nine repeats of a nonapeptide (A/PPGGPYGGP). Peflin may modulate the function of ALG-2 in Ca2+ signaling. It exists only as a heterodimer with ALG-2, and binds two Ca2+ ions through its EF1 and EF3 hands. Its additional EF5 hand is unpaired and does not bind Ca2+ ion but mediates the heterodimerization with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+.

Pssm-ID: 320055 [Multi-domain] Cd Length: 164 Bit Score: 74.87 E-value: 7.33e-18

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   4 EFKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEE-LDAIIEEVDEDGSGTIDFEEF--LVMMVRQMKEdakgkseee 80
Cdd:cd16180    1 ELRRIFQAVDRDRSGRISAKELQRALSNGDWTPFSIEtVRLMINMFDRDRSGTINFDEFvgLWKYIQDWRR--------- 71

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 768018237  81 laeCFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMM 141
Cdd:cd16180   72 ---LFRRFDRDRSGSIDFNELQNALSSFGYRLSPQFVQLLVRKFDRRRRGSISFDDFVEAC 129

EF-hand, calcium binding motif; A diverse superfamily of calcium sensors and calcium signal modulators; most examples in this alignment model have 2 active canonical EF hands. Ca2+ binding induces a conformational change in the EF-hand motif, leading to the activation or inactivation of target proteins. EF-hands tend to occur in pairs or higher copy numbers.

Pssm-ID: 238008 [Multi-domain] Cd Length: 63 Bit Score: 71.81 E-value: 9.35e-18

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 768018237   4 EFKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMM 65
Cdd:cd00051    1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELM 62

EF-hand, calcium binding motif, found in homologs of mammalian apoptosis-linked gene 2 protein (ALG-2); The family includes some homologs of mammalian apoptosis-linked gene 2 protein (ALG-2) mainly found in lower eukaryotes, such as a parasitic protist Leishmarua major and a cellular slime mold Dictyostelium discoideum. These homologs contains five EF-hand motifs. Due to the presence of unfavorable residues at the Ca2+-coordinating positions, their non-canonical EF4 and EF5 hands may not bind Ca2+. Two Dictyostelium PEF proteins are the prototypes of this family. They may bind to cytoskeletal proteins and/or signal-transducing proteins localized to detergent-resistant membranes named lipid rafts, and occur as monomers or weak homo- or heterodimers like ALG-2. They can serve as a mediator for Ca2+ signaling-related Dictyostehum programmed cell death (PCD).

Pssm-ID: 320060 [Multi-domain] Cd Length: 163 Bit Score: 68.01 E-value: 4.01e-15

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   4 EFKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVM--MVRQMKEdakgkseeel 81
Cdd:cd16185    1 ELRQWFRAVDRDRSGSIDVNELQKALAGGGLLFSLATAEKLIRMFDRDGNGTIDFEEFAALhqFLSNMQN---------- 70

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 768018237  82 aeCFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKM 140
Cdd:cd16185   71 --GFEQRDTSRSGRLDANEVHEALAASGFQLDPPAFQALFRKFDPDRGGSLGFDDYIEL 127

EF-hand domain pair;

Pssm-ID: 463900 [Multi-domain] Cd Length: 67 Bit Score: 62.66 E-value: 4.84e-14

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 768018237   78 EEELAECFRIFDRNADGYIDPEELAEIFRAS--GEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMM 141
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRKLeeGEPLSDEEVEELFKEFDLDKDGRISFEEFLELY 66

EF-hand, calcium binding motif, found in apoptosis-linked gene 2 protein (ALG-2) and similar proteins; ALG-2, also termed programmed cell death protein 6 (PDCD6), or probable calcium-binding protein ALG-2, is one of the prototypic members of the penta EF-hand protein family. It is a widely expressed calcium-binding modulator protein associated with cell proliferation and death, as well as cell survival. ALG-2 acts as a pro-apoptotic factor participating in T cell receptor-, Fas-, and glucocorticoid-induced programmed cell death, and also serves as a useful molecular marker for the prognosis of cancers. Moreover, ALG-2 functions as a calcium ion sensor at endoplasmic reticulum (ER) exit sites, and modulates ER-stress-stimulated cell death and neuronal apoptosis during organ formation. Furthermore, ALG-2 can mediate the pro-apoptotic activity of cisplatin or tumor necrosis factor alpha (TNFalpha) through the down-regulation of nuclear factor-kappaB (NF-kappaB) expression. It also inhibits angiogenesis through PI3K/mTOR/p70S6K pathway by interacting of vascular endothelial growth factor receptor-2 (VEGFR-2). In addition, nuclear ALG-2 may participate in the post-transcriptional regulation of Inositol Trisphosphate Receptor Type 1 (IP3R1) pre-mRNA at least in part by interacting with CHERP (Ca2+ homeostasis endoplasmic reticulum protein) calcium-dependently. ALG-2 contains five serially repeated EF-hand motifs and interacts with various proteins, including ALG-2-interacting protein X (Alix), Fas, annexin XI, death-associated protein kinase 1 (DAPk1), Tumor susceptibility gene 101 (TSG101), Sec31A, phospholipid scramblase 3 (PLSCR3), the P-body component PATL1, and endosomal sorting complex required for transport (ESCRT)-III-related protein IST1, in a calcium-dependent manner. It forms a homodimer in the cell or a heterodimer with its closest paralog peflin. Among the PEF proteins, ALG-2 can bind three Ca2+ ions through its EF1, EF3, and EF5 hands, where it is unique in that its EF5 hand binds Ca2+ ion in a canonical coordination.

Pssm-ID: 320058 [Multi-domain] Cd Length: 165 Bit Score: 64.58 E-value: 7.45e-14

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   9 FDMFDADGGGDISVKELGTVMRMLGQTPTKEE-LDAIIEEVDEDGSGTIDFEEFLvmmvrqmkedAKGKSEEELAECFRI 87
Cdd:cd16183    6 FQRVDKDRSGQISATELQQALSNGTWTPFNPEtVRLMIGMFDRDNSGTINFQEFA----------ALWKYITDWQNCFRS 75

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 768018237  88 FDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEF 137
Cdd:cd16183   76 FDRDNSGNIDKNELKQALTSFGYRLSDQFYDILVRKFDRQGRGTIAFDDF 125

Ca2+-binding protein, EF-hand superfamily [Signal transduction mechanisms];

Pssm-ID: 444056 [Multi-domain] Cd Length: 137 Bit Score: 61.73 E-value: 6.43e-13

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   1 MIAEFKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMvrqmkeDAKGKSEEE 80
Cdd:COG5126   31 FRRLWATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISADEFRRLL------TALGVSEEE 104

                         90       100
                 ....*....|....*....|....*.
gi 768018237  81 LAECFRIFDRNADGYIDPEELAEIFR 106
Cdd:COG5126  105 ADELFARLDTDGDGKISFEEFVAAVR 130

EF-hand motif found in eukaryotic phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11) isozymes; PI-PLC isozymes are signaling enzymes that hydrolyze the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity. Calcium is required for the catalysis. This family corresponds to the four EF-hand motifs containing PI-PLC isozymes, including PI-PLC-beta (1-4), -gamma (1-2), -delta (1,3,4), -epsilon (1), -zeta (1), eta (1-2). Lower eukaryotes such as yeast and slime molds contain only delta-type isozymes. In contrast, other types of isoforms present in higher eukaryotes. This family also includes 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase 1 (PLC1) from fungi. Some homologs from plants contain only two atypical EF-hand motifs and they are not included. All PI-PLC isozymes except sperm-specific PI-PLC-zeta share a core set of domains, including an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core, and a single C2 domain. PI-PLC-zeta lacks the PH domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. Most of EF-hand motifs found in PI-PLCs consist of a helix-loop-helix structure, but lack residues critical to metal binding. Moreover, the EF-hand region of most of PI-PLCs may have an important regulatory function, but it has yet to be identified. However, PI-PLC-zeta is a key exception. It is responsible for Ca2+ oscillations in fertilized oocytes and exhibits a high sensitivity to Ca2+ mediated through its EF-hand domain. In addition, PI-PLC-eta2 shows a canonical EF-loop directing Ca2+-sensitivity and thus can amplify transient Ca2+ signals. Also it appears that PI-PLC-delta1 can regulate the binding of PH domain to PIP2 in a Ca2+-dependent manner through its functionally important EF-hand domains. PI-PLCs can be activated by a variety of extracellular ligands, such as growth factors, hormones, cytokines and lipids. Their activation has been implicated in tumorigenesis and/or metastasis linked to migration, proliferation, growth, inflammation, angiogenesis and actin cytoskeleton reorganization. PI-PLC-beta isozymes are activated by G-protein coupled receptor (GPCR) through different mechanisms. However, PI-PLC-gamma isozymes are activated by receptor tyrosine kinase (RTK), such as Rho and Ras GTPases. In contrast, PI-PLC-epsilon are activated by both GPCR and RTK. PI-PLC-delta1 and PLC-eta 1 are activated by GPCR-mediated calcium mobilization. The activation mechanism for PI-PLC-zeta remains unclear.

Pssm-ID: 320029 [Multi-domain] Cd Length: 137 Bit Score: 60.37 E-value: 1.82e-12

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   5 FKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMVRQMkedakgkSEEELAEC 84
Cdd:cd15898    2 LRRQWIKADKDGDGKLSLKEIKKLLKRLNIRVSEKELKKLFKEVDTNGDGTLTFDEFEELYKSLT-------ERPELEPI 74

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 768018237  85 FRIFDRNADGYIDPEELAEIFRA-SGEHVTDEEIESLMKD-GDKNNDGRIDFDEFLKMM 141
Cdd:cd15898   75 FKKYAGTNRDYMTLEEFIRFLREeQGENVSEEECEELIEKyEPERENRQLSFEGFTNFL 133

EF-hand, calcium binding motif, found in parvalbumin-like EF-hand family; The family includes alpha- and beta-parvalbumins, and a group of uncharacterized calglandulin-like proteins. Parvalbumins are small, acidic, cytosolic EF-hand-containing Ca2+-buffer and Ca2+ transporter/shuttle proteins belonging to EF-hand superfamily. They are expressed by vertebrates in fast-twitch muscle cells, specific neurons of the central and peripheral nervous system, sensory cells of the mammalian auditory organ (Corti's cell), and some other cells, and characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. Thus, they may play an additional role in Mg2+ handling. Moreover, parvalbumins represent one of the major animal allergens. In metal-bound states, parvalbumins possess a rigid and stable tertiary structure and display strong allergenicity. In contrast, the metal-free parvalbumins are intrinsically disordered, and the loss of metal ions results in a conformational change that decreases their IgE binding capacity. Furthermore, parvalbumins have been widely used as a neuronal marker for a variety of functional brain systems. They also function as a Ca2+ shuttle transporting Ca2+ from troponin-C (TnC) to the sarcoplasmic reticulum (SR) Ca2+ pump during muscle relaxation. Thus they may facilitate myocardial relaxation and play important roles in cardiac diastolic dysfunction. Parvalbumins consists of alpha- and beta- sublineages, which can be distinguished on the basis of isoelectric point (pI > 5 for alpha; pI

Pssm-ID: 319994 [Multi-domain] Cd Length: 101 Bit Score: 56.77 E-value: 2.39e-11

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  54 GTIDFEEFLVMMvrqmkeDAKGKSEEELAECFRIFDRNADGYIDPEELAEI---FRASGEHVTDEEIESLMKDGDKNNDG 130
Cdd:cd16251   15 GSFNYKKFFEHV------GLKQKSEDQIKKVFQILDKDKSGFIEEEELKYIlkgFSIAGRDLTDEETKALLAAGDTDGDG 88

                         90
                 ....*....|...
gi 768018237 131 RIDFDEFLKMMEG 143
Cdd:cd16251   89 KIGVEEFATLVAG 101

EF-hand, calcium binding motif, found in alpha-parvalbumin; Alpha-parvalbumin is cytosolic Ca2+/Mg2+-binding protein expressed mainly in fast-twitch skeletal myofibrils, where it may act as a soluble relaxing factor facilitating the Ca2+-mediated relaxation phase. It is also expressed in rapidly firing neurons, particularly GABA-ergic neurons, and thus may confer protection against Ca2+ toxicity. The major role of alpha-parvalbumin is metal buffering and transport of Ca2+. It binds different metal cations, and exhibits very high affinity for Ca2+ and physiologically significant affinity for Mg2+. Alpha-parvalbumin is characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. Both metal ion-binding sites in alpha-parvalbumin are high-affinity sites. Additionally, in contrast to beta-parvalbumin, alpha-parvalbumin is less acidic and has an additional residue in the C-terminal helix.

Pssm-ID: 319997 [Multi-domain] Cd Length: 101 Bit Score: 56.37 E-value: 3.12e-11

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 768018237  74 KGKSEEELAECFRIFDRNADGYIDPEELAEI---FRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMM 141
Cdd:cd16254   29 KKKSADDVKKVFHILDKDKSGFIEEDELKFVlkgFSPDGRDLSDKETKALLAAGDKDGDGKIGIDEFATLV 99

calmodulin; Provisional

Pssm-ID: 185504 [Multi-domain] Cd Length: 149 Bit Score: 55.54 E-value: 1.54e-10

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 768018237   4 EFKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMVRQ 68
Cdd:PTZ00184  85 EIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMMMSK 149

Penta-EF hand, calcium binding motifs, found in PEF calpain family; The PEF calpain family belongs to the second group of penta-EF hand (PEF) proteins. It includes classical (also called conventional or typical) calpain (referring to a calcium-dependent papain-like enzymes, EC 3.4.22.17) large catalytic subunits (CAPN1, 2, 3, 8, 9, 11, 12, 13, 14) and two calpain small subunits (CAPNS1 and CAPNS2), which are largely confined to animals (metazoans). These PEF-containing are nonlysosomal intracellular calcium-activated intracellular cysteine proteases that play important roles in the degradation or functional modulation in a variety of substrates in response to calcium signalling. The classical mu- and m-calpains are heterodimers consisting of homologous but a distinct (large) L-subunit/chain (CAPN1 or CAPN2) and a common (small) S-subunit/chain (CAPNS1 or CAPNS2). These L-subunits (CAPN1 and CAPN2) and S-subunit CAPNS1 are ubiquitously found in all tissues. Other calpains likely consist of an isolated L-subunit/chain alone. Many of them, such as CAPNS2, CAPN3 (in skeletal muscle, or lens), CAPN8 (in stomach), CAPN9 (in digestive tracts), CAPN11 (in testis), CAPN12 (in follicles), are tissue-specific and have specific functions in distinct organs. The L-subunits of similar structure (called CALPA and B) also have been found in Drosophila melanogaster. The S-subunit seems to have a chaperone-like function for proper folding of the L-subunit. The catalytic L-subunits contain a short N-terminal anchor helix, followed by a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2+-binding penta-EF-hand (PEF) domain. The S-subunits only have the PEF domain following an N-terminal Gly-rich hydrophobic domain. The calpains undergo a rearrangement of the protein backbone upon Ca2+-binding.

Pssm-ID: 320057 [Multi-domain] Cd Length: 167 Bit Score: 54.15 E-value: 7.35e-10

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  14 ADGGGDISVKELGTVMR--MLGQTPTKEELD-----AIIEEVDEDGSGTIDFEEFLVMMvrqmkedakgKSEEELAECFR 86
Cdd:cd16182   10 AGEDEEIDAVELQKLLNasLLKDMPKFDGFSletcrSLIALMDTNGSGRLDLEEFKTLW----------SDLKKWQAIFK 79

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 768018237  87 IFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKD-GDKNndGRIDFDEFL 138
Cdd:cd16182   80 KFDTDRSGTLSSYELRKALESAGFHLSNKVLQALVLRyADST--GRITFEDFV 130

XopAW family type III secretion system calcium-binding effector;

Pssm-ID: 469301 [Multi-domain] Cd Length: 227 Bit Score: 53.92 E-value: 1.95e-09

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   9 FDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMV----RQMKEDAKGKSEEELAEc 84
Cdd:NF041410  33 FAKLDSDGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDELAAAAPppppPPDQAPSTELADDLLSA- 111

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 768018237  85 friFDRNADGYIDPEELAEIFRASGehvTDEEIESLMKDGDKNNDGRIDFDEF 137
Cdd:NF041410 112 ---LDTDGDGSISSDELSAGLTSAG---SSADSSQLFSALDSDGDGSVSSDEL 158

Ca2+-binding protein, EF-hand superfamily [Signal transduction mechanisms];

Pssm-ID: 444056 [Multi-domain] Cd Length: 137 Bit Score: 51.72 E-value: 3.21e-09

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 768018237   1 MIAEFKAAFDMFDADGGGDISVKELGTVMRMLGqtPTKEELDAIIEEVDEDGSGTIDFEEFLVMMVRQMKEDA 73
Cdd:COG5126   67 VEPFARAAFDLLDTDGDGKISADEFRRLLTALG--VSEEEADELFARLDTDGDGKISFEEFVAAVRDYYTPDA 137

EF-hand, calcium binding motif, found in beta-parvalbumin; Beta-parvalbumin, also termed Oncomodulin-1 (OM), is a small calcium-binding protein that is expressed in hepatomas, as well as in the blastocyst and the cytotrophoblasts of the placenta. It is also found to be expressed in the cochlear outer hair cells of the organ of Corti and frequently expressed in neoplasms. Mammalian beta-parvalbumin is secreted by activated macrophages and neutrophils. It may function as a tissue-specific Ca2+-dependent regulatory protein, and may also serve as a specialized cytosolic Ca2+ buffer. Beta-parvalbumin acts as a potent growth-promoting signal between the innate immune system and neurons in vivo. It has high and specific affinity for its receptor on retinal ganglion cells (RGC) and functions as the principal mediator of optic nerve regeneration. It exerts its effects in a cyclic adenosine monophosphate (cAMP)-dependent manner and can further elevate intracellular cAMP levels. Moreover, beta-parvalbumin is associated with efferent function and outer hair cell electromotility, and can identify different hair cell types in the mammalian inner ear. Beta-parvalbumin is characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. The EF site displays a high-affinity for Ca2+/Mg2+, and the CD site is a low-affinity Ca2+-specific site. In addition, beta-parvalbumin is distinguished from other parvalbumins by its unusually low isoelectric point (pI = 3.1) and sequence eccentricities (e.g., Y57-L58-D59 instead of F57-I58-E59).

Pssm-ID: 319998 [Multi-domain] Cd Length: 101 Bit Score: 50.88 E-value: 3.29e-09

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 768018237  75 GKSEEELAECFRIFDRNADGYIDPEELA---EIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKM 140
Cdd:cd16255   30 KKSADDVKKVFEIIDQDKSGFIEEEELKlflQNFSSGARELTDAETKAFLKAGDSDGDGKIGVEEFQAL 98

EF-hand, calcium binding motif, found in peflin and similar proteins; Peflin, also termed penta-EF hand (PEF) protein with a long N-terminal hydrophobic domain, or penta-EF hand domain-containing protein 1, is a ubiquitously expressed 30-kD PEF protein containing five EF-hand motifs in its C-terminal domain and a longer N-terminal hydrophobic domain (NHB domain) than any other member of the PEF family. The NHB domain harbors nine repeats of a nonapeptide (A/PPGGPYGGP). Peflin may modulate the function of ALG-2 in Ca2+ signaling. It exists only as a heterodimer with ALG-2, and binds two Ca2+ ions through its EF1 and EF3 hands. Its additional EF5 hand is unpaired and does not bind Ca2+ ion but mediates the heterodimerization with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+. In lower vertebrates, peflin may interact with transient receptor potential N (TRPN1), suggesting a potential role of peflin in fast transducer channel adaptation.

Pssm-ID: 320059 [Multi-domain] Cd Length: 165 Bit Score: 51.88 E-value: 4.37e-09

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   9 FDMFDADGGGDISVKEL-GTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEF--LVMMVRQMKEdakgkseeelaeCF 85
Cdd:cd16184    6 FQAVDRDRSGKISAKELqQALVNGNWSHFNDETCRLMIGMFDKDKSGTIDIYEFqaLWNYIQQWKQ------------VF 73

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|..
gi 768018237  86 RIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEF 137
Cdd:cd16184   74 QQFDRDRSGSIDENELHQALSQMGYRLSPQFVQFLVSKYDPRARRSLTLDQF 125

The penta-EF hand (PEF) family; The penta-EF hand (PEF) family contains a group of five EF-hand calcium-binding proteins, including several classical calpain large catalytic subunits (CAPN1, 2, 3, 8, 9, 11, 12, 13, 14), two calpain small subunits (CAPNS1 and CAPNS2), as well as non-calpain PEF proteins, ALG-2 (apoptosis-linked gene 2, also termed programmed cell death protein 6, PDCD6), peflin, sorcin, and grancalcin. Based on the sequence similarity of EF1 hand, ALG-2 and peflin have been classified into group I PEF proteins. Calcium-dependent protease calpain subfamily members, sorcin and grancalcin, are group II PEF proteins. Calpains (EC 3.4.22.17) are calcium-activated intracellular cysteine proteases that play important roles in the degradation or functional modulation in a variety of substrates. They have been implicated in a number of physiological processes such as cell cycle progression, remodeling of cytoskeletal-cell membrane attachments, signal transduction, gene expression and apoptosis. ALG-2 is a pro-apoptotic factor that forms a homodimer in the cell or a heterodimer with its closest paralog peflin through their EF5s. Peflin is a 30-kD PEF protein with a longer N-terminal hydrophobic domain than any other member of the PEF family, and it contains nine nonapeptide (A/PPGGPYGGP) repeats. It exists only as a heterodimer with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+. ALG-2 interacts with various proteins in a Ca2+-dependent manner. Sorcin (for soluble resistance-related calcium binding protein) is a soluble resistance-related calcium-binding protein that participates in the regulation of calcium homeostasis in cells. Grancalcin is a cytosolic Ca2+-binding protein specifically expressed in neutrophils and monocytes/macrophages. It plays a key role in leukocyte-specific functions that are responsible for host defense. Grancalcin can form a heterodimer together with sorcin. Members in this family contain five EF-hand motifs attached to an N-terminal region of variable length containing one or more short Gly/Pro-rich sequences. These proteins form homodimers or heterodimers through pairing between the 5th EF-hands from the two molecules. Unlike calmodulin, the PEF domains do not undergo major conformational changes upon binding Ca2+.

Pssm-ID: 320054 [Multi-domain] Cd Length: 165 Bit Score: 51.66 E-value: 5.77e-09

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  14 ADGGGDISVKELGTVMRMLGQTPTK-----EELDAIIEEVDEDGSGTIDFEEF--LVMMVRQMKEDakgkseeelaecFR 86
Cdd:cd15897   10 AGDDGEISATELQQALSNVGWTHFDlgfslETCRSMIAMMDRDHSGKLNFSEFkgLWNYIKAWQEI------------FR 77

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|..
gi 768018237  87 IFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNdGRIDFDEFL 138
Cdd:cd15897   78 TYDTDGSGTIDSNELRQALSGAGYRLSEQTYDIIIRRYDRGR-GNIDFDDFI 128

EF-hand, calcium binding motif, found in the hexa-EF hand proteins family; The hexa-EF hand proteins family, also named the calbindin sub-family, contains a group of six EF-hand Ca2+-binding proteins, including calretinin (CR, also termed 29 kDa calbindin), calbindin D28K (CB, also termed vitamin D-dependent calcium-binding protein, avian-type), and secretagogin (SCGN). CR is a cytosolic hexa-EF-hand calcium-binding protein predominantly expressed in a variety of normal and tumorigenic t-specific neurons of the central and peripheral nervous system. It is a multifunctional protein implicated in many biological processes, including cell proliferation, differentiation, and cell death. CB is highly expressed in brain tissue. It is a strong calcium-binding and buffering protein responsible for preventing a neuronal death as well as maintaining and controlling calcium homeostasis. SCGN is a six EF-hand calcium-binding protein expressed in neuroendocrine, pancreatic endocrine and retinal cells. It plays a crucial role in cell apoptosis, receptor signaling and differentiation. It is also involved in vesicle secretion through binding to various proteins, including interacts with SNAP25, SNAP23, DOC2alpha, ARFGAP2, rootletin, KIF5B, beta-tubulin, DDAH-2, ATP-synthase and myeloid leukemia factor 2. SCGN functions as a Ca2+ sensor/coincidence detector modulating vesicular exocytosis of neurotransmitters, neuropeptides or hormones. Although the family members share a significant amount of secondary sequence homology, they display altered structural and biochemical characteristics, and operate in distinct fashions. CB contains six EF-hand motifs in a single globular domain, where EF-hands 1, 3, 4, 5 bind four calcium ions. CR contains six EF-hand motifs within two independent domains, CR I-II and CR III-VI. They harbor two and four EF-hand motifs, respectively. The first 5 EF-hand motifs are capable of binding calcium ions, while the EF-hand 6 is inactive. SCGN consists of the three globular domains each of which contains a pair of EF-hand motifs. Human SCGN simultaneously binds four calcium ions through its EF-hands 3, 4, 5 and 6 in one high affinity and three low affinity calcium-binding sites. In contrast, SCGNs in other lower eukaryotes, such as D. rerio, X. laevis, M. domestica, G. gallus, O. anatinus, are fully competent in terms of six calcium-binding.

Pssm-ID: 320075 [Multi-domain] Cd Length: 254 Bit Score: 52.36 E-value: 7.20e-09

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   9 FDMFDADGGGDISVKELGTVMRMLGQTPTKEELDA---------IIEEVDEDGSGTIDFEEFLVMMV------RQMKEDA 73
Cdd:cd15902    5 WMHFDADGNGYIEGKELDSFLRELLKALNGKDKTDdevaekkkeFMEKYDENEDGKIEIRELANILPteenflLLFRREQ 84

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 768018237  74 KGKSEEELAECFRIFDRNADGYIDPEELAEIFR--------ASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMM 141
Cdd:cd15902   85 PLISSVEFMKIWRKYDTDGSGFIEAKELKGFLKdlllknkkHVSPPKLDEYTKLILKEFDANKDGKLELDEMAKLL 160

Penta-EF hand, calcium binding motifs, found in sorcin, grancalcin, and similar proteins; The family corresponds to the second group of penta-EF hand (PEF) proteins that includes sorcin, grancalcin, and similar proteins. Sorcin, also termed 22 kDa Ca2+-binding protein, CP-22, or V19, is a soluble resistance-related calcium-binding protein that is expressed in normal mammalian tissues, such as the liver, lungs and heart. It contains a flexible glycine and proline-rich N-terminal extension and five EF-hand motifs that associate with membranes in a calcium-dependent manner. It may harbor three potential Ca2+ binding sites through its EF1, EF2 and EF3 hands. However, binding of only two Ca2+/monomer suffices to trigger the conformational change that exposes hydrophobic regions and leads to interaction with the respective targets. Sorcin forms homodimers through the association of the unpaired EF5 hand. Among the PEF proteins, sorcin is unique in that it contains potential phosphorylation sites by cAMP-dependent protein kinase (PKA), and it can form a tetramer at slightly acid pH values although remaining a stable dimer at neutral pH. Grancalcin (GCA) is a cytosolic Ca2+-binding protein specifically expressed in neutrophils and monocytes/macrophages. It can strongly interact with sorcin to form a heterodimer and further modulate the function of sorcin. GCA exists as homodimers in solution. It contains five EF-hand motifs attached to an N-terminal region of an approximately 50 residue-long segment rich in glycines and prolines. In contrast with sorcin, GCA binds two Ca2+ ions through its EF1 and EF3 hands.

Pssm-ID: 320056 [Multi-domain] Cd Length: 165 Bit Score: 50.83 E-value: 1.33e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  12 FDADGG--GDISVKELGTVMRMLG-----QTPTKEELDAIIEEVDEDGSGTIDFEEF--LVMMVRQMKEDakgkseeela 82
Cdd:cd16181    6 FSAVAGqdGQIDADELQRCLTQSGisgnyQPFSLETCRLMIAMLDRDHSGKMGFNEFkeLWAALNQWKTT---------- 75

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 768018237  83 ecFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNndGRIDFDEFL 138
Cdd:cd16181   76 --FMQYDRDRSGTVEPQELQQAIRSFGYNLSPQALNVIVKRYSKN--GRITFDDFV 127

EF-hand domain pair;

Pssm-ID: 463900 [Multi-domain] Cd Length: 67 Bit Score: 48.02 E-value: 2.25e-08

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 768018237    6 KAAFDMFDADGGGDISVKELGTVMRML--GQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMM 65
Cdd:pfam13499   5 KEAFKLLDSDGDGYLDVEELKKLLRKLeeGEPLSDEEVEELFKEFDLDKDGRISFEEFLELY 66

Ca2+-binding protein, EF-hand superfamily [Signal transduction mechanisms];

Pssm-ID: 444056 [Multi-domain] Cd Length: 137 Bit Score: 48.63 E-value: 5.57e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  38 KEELDAIIEEVDEDGSGTIDFEEFLVMMVRQmkedakgkseeeLAECFRIFDRNADGYIDPEELAEIFRASGEHVTDEEI 117
Cdd:COG5126    4 RRKLDRRFDLLDADGDGVLERDDFEALFRRL------------WATLFSEADTDGDGRISREEFVAGMESLFEATVEPFA 71

                         90       100
                 ....*....|....*....|....*.
gi 768018237 118 ESLMKDGDKNNDGRIDFDEFLKMMEG 143
Cdd:COG5126   72 RAAFDLLDTDGDGKISADEFRRLLTA 97

EF-hand motif found in eukaryotic phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11) isozymes; PI-PLC isozymes are signaling enzymes that hydrolyze the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity. Calcium is required for the catalysis. This family corresponds to the four EF-hand motifs containing PI-PLC isozymes, including PI-PLC-beta (1-4), -gamma (1-2), -delta (1,3,4), -epsilon (1), -zeta (1), eta (1-2). Lower eukaryotes such as yeast and slime molds contain only delta-type isozymes. In contrast, other types of isoforms present in higher eukaryotes. This family also includes 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase 1 (PLC1) from fungi. Some homologs from plants contain only two atypical EF-hand motifs and they are not included. All PI-PLC isozymes except sperm-specific PI-PLC-zeta share a core set of domains, including an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core, and a single C2 domain. PI-PLC-zeta lacks the PH domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. Most of EF-hand motifs found in PI-PLCs consist of a helix-loop-helix structure, but lack residues critical to metal binding. Moreover, the EF-hand region of most of PI-PLCs may have an important regulatory function, but it has yet to be identified. However, PI-PLC-zeta is a key exception. It is responsible for Ca2+ oscillations in fertilized oocytes and exhibits a high sensitivity to Ca2+ mediated through its EF-hand domain. In addition, PI-PLC-eta2 shows a canonical EF-loop directing Ca2+-sensitivity and thus can amplify transient Ca2+ signals. Also it appears that PI-PLC-delta1 can regulate the binding of PH domain to PIP2 in a Ca2+-dependent manner through its functionally important EF-hand domains. PI-PLCs can be activated by a variety of extracellular ligands, such as growth factors, hormones, cytokines and lipids. Their activation has been implicated in tumorigenesis and/or metastasis linked to migration, proliferation, growth, inflammation, angiogenesis and actin cytoskeleton reorganization. PI-PLC-beta isozymes are activated by G-protein coupled receptor (GPCR) through different mechanisms. However, PI-PLC-gamma isozymes are activated by receptor tyrosine kinase (RTK), such as Rho and Ras GTPases. In contrast, PI-PLC-epsilon are activated by both GPCR and RTK. PI-PLC-delta1 and PLC-eta 1 are activated by GPCR-mediated calcium mobilization. The activation mechanism for PI-PLC-zeta remains unclear.

Pssm-ID: 320029 [Multi-domain] Cd Length: 137 Bit Score: 48.43 E-value: 5.95e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  41 LDAIIEEVDEDGSGTIDFEEflvmMVRQMKEDAKGKSEEELAECFRIFDRNADGYIDPEELAEIFRasgEHVTDEEIESL 120
Cdd:cd15898    2 LRRQWIKADKDGDGKLSLKE----IKKLLKRLNIRVSEKELKKLFKEVDTNGDGTLTFDEFEELYK---SLTERPELEPI 74

                         90       100
                 ....*....|....*....|....*
gi 768018237 121 MKDGDKNNDGRIDFDEFLKMMEGVQ 145
Cdd:cd15898   75 FKKYAGTNRDYMTLEEFIRFLREEQ 99

EF-hand, calcium binding motif, found in CREC-EF hand family; The CREC (Cab45/reticulocalbin/ERC45/calumenin)-EF hand family contains a group of six EF-hand, low-affinity Ca2+-binding proteins, including reticulocalbin (RCN-1), ER Ca2+-binding protein of 55 kDa (ERC-55, also known as TCBP-49 or E6BP), reticulocalbin-3 (RCN-3), Ca2+-binding protein of 45 kDa (Cab45 and its splice variant Cab45b), and calumenin ( also known as crocalbin or CBP-50). The proteins are not only localized in various parts of the secretory pathway, but also found in the cytosolic compartment and at the cell surface. They interact with different ligands or proteins and have been implicated in the secretory process, chaperone activity, signal transduction as well as in a large variety of disease processes.

Pssm-ID: 320021 [Multi-domain] Cd Length: 267 Bit Score: 49.36 E-value: 1.07e-07

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  44 IIEEVDEDGSGTIDFEEFLVMMVR-QMKEDAKGKSEEELAECFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMK 122
Cdd:cd15899  165 TLEDLDKNGDGFISLEEFISDPYSaDENEEEPEWVKVEKERFVELRDKDKDGKLDGEELLSWVDPSNQEIALEEAKHLIA 244

                         90
                 ....*....|....*..
gi 768018237 123 DGDKNNDGRIDFDEFLK 139
Cdd:cd15899  245 ESDENKDGKLSPEEILD 261

EF-hand, calcium binding motif, found in mitochondrial calcium uptake proteins MICU1, MICU2, MICU3, and similar proteins; This family includes mitochondrial calcium uptake protein MICU1 and its two additional paralogs, MICU2 and MICU3. MICU1 localizes to the inner mitochondrial membrane (IMM). It functions as a gatekeeper of the mitochondrial calcium uniporter (MCU) and regulates MCU-mediated mitochondrial Ca2+ uptake, which is essential for maintaining mitochondrial homoeostasis. MICU1 and MICU2 are physically associated within the uniporter complex and are co-expressed across all tissues. They may play non-redundant roles in the regulation of the mitochondrial calcium uniporter. At present, the precise molecular function of MICU2 and MICU3 remain unclear. MICU2 may play possible roles in Ca2+ sensing and regulation of MCU, calcium buffering with a secondary impact on transport or assembly and stabilization of MCU. MICU3 likely has a role in mitochondrial calcium handling. All members in this family contains an N-terminal mitochondrial targeting sequence (MTS) as well as two evolutionarily conserved canonical Ca2+-binding EF-hands separated by a long stretch of residues predicted to form alpha-helices.

Pssm-ID: 320080 [Multi-domain] Cd Length: 152 Bit Score: 47.61 E-value: 1.51e-07

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   5 FKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVD----------------EDGSGTIDFEEFLVMMVRQ 68
Cdd:cd15900    2 FEIAFKMFDLDGDGELDKEEFNKVQSIIRSQTSVGQRHRDHTNGEstklgmnstlaryffgKDGKQKLSIEKFLEFQENL 81

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 768018237  69 MKEdakgksEEELAECFRIFdRNADGYIDPEELAEIFRAS-GEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMM 141
Cdd:cd15900   82 QEE------IDDVDTALTFY-HLAGASIDRKTFKRAAKVVaGVELSDHVVDVVFTIFDEDGDGILSHKEFISVM 148

EF-hand, calcium binding motif, found in parvalbumins; Parvalbumins are small, acidic, cytosolic EF-hand-containing Ca2+-buffer and Ca2+ transporter/shuttle proteins belonging to EF-hand superfamily. They are expressed by vertebrates in fast-twitch muscle cells, specific neurons of the central and peripheral nervous system, sensory cells of the mammalian auditory organ (Corti's cell), and some other cells, and characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. Thus, they may play an additional role in Mg2+ handling. Moreover, parvalbumins represent one of the major animal allergens. In metal-bound states, parvalbumins possess a rigid and stable tertiary structure and display strong allergenicity. In contrast, the metal-free parvalbumins are intrinsically disordered, and the loss of metal ions results in a conformational change that decreases their IgE binding capacity. Furthermore, parvalbumins have been widely used as a neuronal marker for a variety of functional brain systems. They also function as a Ca2+ shuttle transporting Ca2+ from troponin-C (TnC) to the sarcoplasmic reticulum (SR) Ca2+ pump during muscle relaxation. Thus they may facilitate myocardial relaxation and play important roles in cardiac diastolic dysfunction. Parvalbumins consists of alpha- and beta- sublineages, which can be distinguished on the basis of isoelectric point (pI > 5 for alpha; pI

Pssm-ID: 319996 [Multi-domain] Cd Length: 101 Bit Score: 46.40 E-value: 2.11e-07

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  74 KGKSEEELAECFRIFDRNADGYIDPEELAEI---FRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKM 140
Cdd:cd16253   29 SKKSPADIKKVFNILDQDKSGFIEEEELKLFlknFSDGARVLSDKETKNFLAAGDSDGDGKIGVDEFKSM 98

XopAW family type III secretion system calcium-binding effector;

Pssm-ID: 469301 [Multi-domain] Cd Length: 227 Bit Score: 48.14 E-value: 2.32e-07

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   6 KAAFDMFDADGGGDISVKELGTVMRM----LGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMvrqmkedAKGKSEEEL 81
Cdd:NF041410  66 SELFSDLDSDGDGSLSSDELAAAAPPppppPDQAPSTELADDLLSALDTDGDGSISSDELSAGL-------TSAGSSADS 138

                         90       100
                 ....*....|....*....|.
gi 768018237  82 AECFRIFDRNADGYIDPEELA 102
Cdd:NF041410 139 SQLFSALDSDGDGSVSSDELA 159

EF-hand, calcium binding motif, found in reticulocalbin-2 (RCN2) mainly from protostomes; This family corresponds to a group of uncharacterized RCN2-like proteins, which are mainly found in protostomes. Although their biological function remains unclear, they show high sequence similarity with RCN2 (also known as E6BP or TCBP-49), which is an endoplasmic reticulum resident low-affinity Ca2+-binding protein that has been implicated in immunity, redox homeostasis, cell cycle regulation and coagulation. Members in this family contain six copies of the EF-hand Ca2+-binding motif, but may lack a C-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide that is required for retention of RCN2 in the endoplasmic reticulum (ER).

Pssm-ID: 320025 [Multi-domain] Cd Length: 263 Bit Score: 46.93 E-value: 6.19e-07

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   9 FDMFDADGGGDISVKELGTV----MRMLGQTPTKEELdaiiEEVDEDGSGTIDFEEFLV----MMVRQMKEDAKGKSEEE 80
Cdd:cd16227   42 AKKMDLNDDGFIDRKELKAWilrsFKMLDEEEANERF----EEADEDGDGKVTWEEYLAdsfgYDDEDNEEMIKDSTEDD 117

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 768018237  81 L------AECFRIFDRNADGYIDPEELAEIFRA-SGEHVTDEEIESLMKDGDKNNDGRIDFDEFL 138
Cdd:cd16227  118 LklleddKEMFEAADLNKDGKLDKTEFSAFQHPeEYPHMHPVLIEQTLRDKDKDNDGFISFQEFL 182

EF-hand, calcium binding motif, found in calbindin (CB); CB, also termed calbindin D28, or D-28K, or avian-type vitamin D-dependent calcium-binding protein, is a unique intracellular calcium binding protein that functions as both a calcium sensor and buffer in eukaryotic cells, which undergoes a conformational change upon calcium binding and protects cells against insults of high intracellular calcium concentration. CB is highly expressed in brain and sensory neurons. It plays essential roles in neural functioning, altering synaptic interactions in the hippocampus, modulating calcium channel activity, calcium transients, and intrinsic neuronal firing activity. It prevents a neuronal death, as well as maintains and controls calcium homeostasis. CB also modulates the activity of proteins participating in the development of neurodegenerative disorders such as Alzheimer's disease, Huntington's disease, and bipolar disorder. Moreover, CB interacts with Ran-binding protein M, a protein known to involve in microtubule function. It also interacts with alkaline phosphatase and myo-inositol monophosphatase, as well as caspase 3, an enzyme that plays an important role in the regulation of apoptosis. CB contains six EF-hand motifs in a single globular domain, where EF-hands 1, 3, 4, 5 bind four calcium ions with high affinity.

Pssm-ID: 320076 [Multi-domain] Cd Length: 243 Bit Score: 46.76 E-value: 6.33e-07

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  12 FDADGGGDISVKELGTVMRMLGQTPTK------EELDAIIEEVDEDGSGTIDF----------EEFLVMMVRQMKedakg 75
Cdd:cd16176    8 YDNDGNGYIEGKELQSFIQELQQARKKaglelsDQMKAFVDQYGQSTDGKIGIvelaqilpteENFLLFFRQQLK----- 82

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 768018237  76 kSEEELAECFRIFDRNADGYIDPEELAEIF--------RASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMM 141
Cdd:cd16176   83 -SSEEFMQTWRKYDADHSGFIEADELKSFLkdllkkanKPFDESKLEEYTHTMLKMFDSNNDGKLGLTEMARLL 155

EF-hand, calcium binding motif, found in apoptosis-linked gene 2 protein (ALG-2) and similar proteins; ALG-2, also termed programmed cell death protein 6 (PDCD6), or probable calcium-binding protein ALG-2, is one of the prototypic members of the penta EF-hand protein family. It is a widely expressed calcium-binding modulator protein associated with cell proliferation and death, as well as cell survival. ALG-2 acts as a pro-apoptotic factor participating in T cell receptor-, Fas-, and glucocorticoid-induced programmed cell death, and also serves as a useful molecular marker for the prognosis of cancers. Moreover, ALG-2 functions as a calcium ion sensor at endoplasmic reticulum (ER) exit sites, and modulates ER-stress-stimulated cell death and neuronal apoptosis during organ formation. Furthermore, ALG-2 can mediate the pro-apoptotic activity of cisplatin or tumor necrosis factor alpha (TNFalpha) through the down-regulation of nuclear factor-kappaB (NF-kappaB) expression. It also inhibits angiogenesis through PI3K/mTOR/p70S6K pathway by interacting of vascular endothelial growth factor receptor-2 (VEGFR-2). In addition, nuclear ALG-2 may participate in the post-transcriptional regulation of Inositol Trisphosphate Receptor Type 1 (IP3R1) pre-mRNA at least in part by interacting with CHERP (Ca2+ homeostasis endoplasmic reticulum protein) calcium-dependently. ALG-2 contains five serially repeated EF-hand motifs and interacts with various proteins, including ALG-2-interacting protein X (Alix), Fas, annexin XI, death-associated protein kinase 1 (DAPk1), Tumor susceptibility gene 101 (TSG101), Sec31A, phospholipid scramblase 3 (PLSCR3), the P-body component PATL1, and endosomal sorting complex required for transport (ESCRT)-III-related protein IST1, in a calcium-dependent manner. It forms a homodimer in the cell or a heterodimer with its closest paralog peflin. Among the PEF proteins, ALG-2 can bind three Ca2+ ions through its EF1, EF3, and EF5 hands, where it is unique in that its EF5 hand binds Ca2+ ion in a canonical coordination.

Pssm-ID: 320058 [Multi-domain] Cd Length: 165 Bit Score: 45.71 E-value: 9.15e-07

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   2 IAEFKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFL---VMMVRqmkedakgkse 78
Cdd:cd16183   66 ITDWQNCFRSFDRDNSGNIDKNELKQALTSFGYRLSDQFYDILVRKFDRQGRGTIAFDDFIqccVVLQT----------- 134

                         90
                 ....*....|....*....
gi 768018237  79 eeLAECFRIFDRNADGYID 97
Cdd:cd16183  135 --LTDSFRRYDTDQDGWIQ 151

EF-hand, calcium binding motif, found in secretagogin (SCGN); SCGN is a six EF-hand calcium-binding protein expressed in neuroendocrine, pancreatic endocrine and retinal cells. It plays a crucial role in cell apoptosis, receptor signaling and differentiation. It is also involved in vesicle secretion through binding to various proteins, including interacts with SNAP25, SNAP23, DOC2alpha, ARFGAP2, rootletin, KIF5B, beta-tubulin, DDAH-2, ATP-synthase and myeloid leukemia factor 2. SCGN functions as a calcium sensor/coincidence detector modulating vesicular exocytosis of neurotransmitters, neuropeptides or hormones. It also serves as a calcium buffer in neurons. Thus, SCGN may be linked to the pathogenesis of neurological diseases such as Alzheimer's, and also acts as a serum marker of neuronal damage, or as a tumor biomarker. SCGN consists of the three globular domains each of which contains a pair of EF-hand motifs. All six EF hand motifs of SCGN in some eukaryotes, including D. rerio, X. laevis, M. domestica, G. gallus, O. anatinus, could potentially bind six calcium ions. In contrast, SCGNs from higher eukaryotes have at least one non-functional EF-hand motif due to the mutation(s) or deletions. For instance, the EF1 loop does not coordinate calcium ion due to the key residue asparagine replaced by lysine in SCGNs of many mammalian species. Moreover, the EF2 loop seems to be competent for calcium-binding in most mammalian SCGNs except for human and chimpanzee orthologs.

Pssm-ID: 320078 [Multi-domain] Cd Length: 257 Bit Score: 46.24 E-value: 1.21e-06

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   5 FKAAFDMFDADGGGDISVKELGTVMRMLGQ------TPTKEELDAIIEEV----DEDGSGTIDFEEFLVMMVRQ------ 68
Cdd:cd16178    1 FAEIWQHFDADESGYIEGKELDNFFKDLLKklgtkdTISADEVQDVKECFmsayDVTGDGRIQIQELANIILPDdenfll 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  69 -MKEDAKGKSEEELAECFRIFDRNADGYIDPEEL----AEIFRASGEHVTDEEIE----SLMKDGDKNNDGRIDFDEFLK 139
Cdd:cd16178   81 fFRREEPLDSSVEFMRIWRKYDADSSGYISAAELknflRDLFLQHKKVITEDKLDeytdTMMKIFDKNKDGRLDLNDMAR 160


                 ..
gi 768018237 140 MM 141
Cdd:cd16178  161 IL 162

EF-hand domain pair;

Pssm-ID: 404678 [Multi-domain] Cd Length: 54 Bit Score: 42.69 E-value: 1.78e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 768018237   93 DGYIDPEELAEIFRASG-EHVTDEEIESLMKDGDKNNDGRIDFDEFLKMME 142
Cdd:pfam13833   2 KGVITREELKRALALLGlKDLSEDEVDILFREFDTDGDGYISFDEFCVLLE 52

EF-hand, calcium binding motif, found in reticulocalbin-2 (RCN2); RCN2, also termed calcium-binding protein ERC-55, or E6-binding protein (E6BP), or TCBP-49, is an endoplasmic reticulum resident low-affinity Ca2+-binding protein that has been implicated in immunity, redox homeostasis, cell cycle regulation and coagulation. It is associated with tumorigenesis, in particular with transformation of cells of the cervix induced by human papillomavirus (HPV), through binding to human papillomavirus (HPV) E6 oncogenic protein. It specifically interacts with vitamin D receptor among nuclear receptors. RCN2 contains an N-terminal signal sequence followed by six copies of the EF-hand Ca2+-binding motif, and a C-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide that is required for retention of RCN2 in the endoplasmic reticulum (ER).

Pssm-ID: 320022 [Multi-domain] Cd Length: 268 Bit Score: 45.50 E-value: 2.23e-06

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  45 IEEVDEDGSGTIDFEEFLVMMVR--QMKEDAKGKSEEELaECFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMK 122
Cdd:cd16224  167 LEEHDKDGDGFISLEEFLGDYRKdpTANEDPEWIIVEKD-RFVNDYDKDNDGKLDPQELLPWVVPNNYGIAQEEALHLID 245

                         90       100
                 ....*....|....*....|
gi 768018237 123 DGDKNNDGRIDFDEFLKMME 142
Cdd:cd16224  246 EMDLNGDGRLSEEEILENQD 265

EF-hand domain pair;

Pssm-ID: 404678 [Multi-domain] Cd Length: 54 Bit Score: 42.30 E-value: 2.36e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 768018237   16 GGGDISVKELGTVMRMLG-QTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMVRQ 68
Cdd:pfam13833   1 EKGVITREELKRALALLGlKDLSEDEVDILFREFDTDGDGYISFDEFCVLLERR 54

EF-hand, calcium binding motif, found in the hexa-EF hand proteins family; The hexa-EF hand proteins family, also named the calbindin sub-family, contains a group of six EF-hand Ca2+-binding proteins, including calretinin (CR, also termed 29 kDa calbindin), calbindin D28K (CB, also termed vitamin D-dependent calcium-binding protein, avian-type), and secretagogin (SCGN). CR is a cytosolic hexa-EF-hand calcium-binding protein predominantly expressed in a variety of normal and tumorigenic t-specific neurons of the central and peripheral nervous system. It is a multifunctional protein implicated in many biological processes, including cell proliferation, differentiation, and cell death. CB is highly expressed in brain tissue. It is a strong calcium-binding and buffering protein responsible for preventing a neuronal death as well as maintaining and controlling calcium homeostasis. SCGN is a six EF-hand calcium-binding protein expressed in neuroendocrine, pancreatic endocrine and retinal cells. It plays a crucial role in cell apoptosis, receptor signaling and differentiation. It is also involved in vesicle secretion through binding to various proteins, including interacts with SNAP25, SNAP23, DOC2alpha, ARFGAP2, rootletin, KIF5B, beta-tubulin, DDAH-2, ATP-synthase and myeloid leukemia factor 2. SCGN functions as a Ca2+ sensor/coincidence detector modulating vesicular exocytosis of neurotransmitters, neuropeptides or hormones. Although the family members share a significant amount of secondary sequence homology, they display altered structural and biochemical characteristics, and operate in distinct fashions. CB contains six EF-hand motifs in a single globular domain, where EF-hands 1, 3, 4, 5 bind four calcium ions. CR contains six EF-hand motifs within two independent domains, CR I-II and CR III-VI. They harbor two and four EF-hand motifs, respectively. The first 5 EF-hand motifs are capable of binding calcium ions, while the EF-hand 6 is inactive. SCGN consists of the three globular domains each of which contains a pair of EF-hand motifs. Human SCGN simultaneously binds four calcium ions through its EF-hands 3, 4, 5 and 6 in one high affinity and three low affinity calcium-binding sites. In contrast, SCGNs in other lower eukaryotes, such as D. rerio, X. laevis, M. domestica, G. gallus, O. anatinus, are fully competent in terms of six calcium-binding.

Pssm-ID: 320075 [Multi-domain] Cd Length: 254 Bit Score: 45.42 E-value: 2.40e-06

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   3 AEFKAAFDMFDADGGGDISVKELGTVMRML--------GQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMVRQMKEDAK 74
Cdd:cd15902   90 VEFMKIWRKYDTDGSGFIEAKELKGFLKDLllknkkhvSPPKLDEYTKLILKEFDANKDGKLELDEMAKLLPVQENFLLK 169

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 768018237  75 GK-------SEEELAECFRIFDRNADGYIDPEELAEIFRASGEHVTDEE--------IESLMKDGDKNNDGRIDFDE 136
Cdd:cd15902  170 FQilgamdlTKEDFEKVFEHYDKDNNGVIEGNELDALLKDLLEKNKADIdkpdlenfRDAILRACDKNKDGKIQKTE 246

Penta-EF hand, calcium binding motifs, found in Group I PEF proteins; The family corresponds to Group I PEF proteins that have been found not only in higher animals but also in lower animals, plants, fungi and protists. Group I PEF proteins include apoptosis-linked gene 2 protein (ALG-2), peflin and similar proteins. ALG-2, also termed programmed cell death protein 6 (PDCD6), is a widely expressed calcium-binding modulator protein associated with cell proliferation and death, as well as cell survival. It forms a homodimer in the cell or a heterodimer with its closest paralog peflin. Among the PEF proteins, ALG-2 can bind three Ca2+ ions through its EF1, EF3, and EF5 hands, where it is unique in that its EF5 hand binds Ca2+ ion in a canonical coordination. Peflin is a ubiquitously expressed 30-kD PEF protein containing five EF-hand motifs in its C-terminal domain and a longer N-terminal hydrophobic domain (NHB domain) than any other member of the PEF family. The NHB domain harbors nine repeats of a nonapeptide (A/PPGGPYGGP). Peflin may modulate the function of ALG-2 in Ca2+ signaling. It exists only as a heterodimer with ALG-2, and binds two Ca2+ ions through its EF1 and EF3 hands. Its additional EF5 hand is unpaired and does not bind Ca2+ ion but mediates the heterodimerization with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+.

Pssm-ID: 320055 [Multi-domain] Cd Length: 164 Bit Score: 44.06 E-value: 3.57e-06

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   2 IAEFKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFL-VMMVRQMkedakgkseee 80
Cdd:cd16180   66 IQDWRRLFRRFDRDRSGSIDFNELQNALSSFGYRLSPQFVQLLVRKFDRRRRGSISFDDFVeACVTLKR----------- 134

                         90
                 ....*....|....*.
gi 768018237  81 LAECFRIFDRNADGYI 96
Cdd:cd16180  135 LTDAFRKYDTNRTGYA 150

EF-hand, calcium binding motif, found in uncharacterized calglandulin-like proteins; The family corresponds to a group of uncharacterized calglandulin-like proteins. Although their biological function remain unclear, they show high sequence similarity with human calglandulin-like protein GAGLP, which is an ortholog of calglandulin from the venom glands of Bothrops insularis snake. Both GAGLP and calglandulin are putative Ca2+-binding proteins with four EF-hand motifs. However, members in this family contain only three EF-hand motifs. In this point, they may belong to the parvalbumin-like EF-hand family, which is characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix).

Pssm-ID: 319995 [Multi-domain] Cd Length: 106 Bit Score: 42.90 E-value: 3.89e-06

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  54 GTIDFEEFLVMMvrqMKEDAKGKSEEELAECFRIFDRNADGYIDPEELAEIFRASGEH-----VTDEEIESLMKDGDKNN 128
Cdd:cd16252   15 GSFNYSKFFEYM---QKFQTSEQQEEAIRKAFQMLDKDKSGFIEWNEIKYILSTVPSSmpvapLSDEEAEAMIQAADTDG 91

                         90
                 ....*....|....*
gi 768018237 129 DGRIDFDEFLKMMEG 143
Cdd:cd16252   92 DGRIDFQEFSDMVKK 106

EF-hand, calcium binding motif, found in reticulocalbin-2 (RCN2) mainly from protostomes; This family corresponds to a group of uncharacterized RCN2-like proteins, which are mainly found in protostomes. Although their biological function remains unclear, they show high sequence similarity with RCN2 (also known as E6BP or TCBP-49), which is an endoplasmic reticulum resident low-affinity Ca2+-binding protein that has been implicated in immunity, redox homeostasis, cell cycle regulation and coagulation. Members in this family contain six copies of the EF-hand Ca2+-binding motif, but may lack a C-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide that is required for retention of RCN2 in the endoplasmic reticulum (ER).

Pssm-ID: 320025 [Multi-domain] Cd Length: 263 Bit Score: 44.23 E-value: 5.22e-06

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  40 ELDAIIEEVDEDGSGTIDFEEFLVMMVRQMKEDAKgKSEEELAEcfRIFDRNADGYIDPEELAEIFRASGEHVTDEEIES 119
Cdd:cd16227  160 LIEQTLRDKDKDNDGFISFQEFLGDRAGHEDKEWL-LVEKDRFD--EDYDKDGDGKLDGEEILSWLVPDNEEIAEEEVDH 236

                         90
                 ....*....|....*....
gi 768018237 120 LMKDGDKNNDGRIDFDEFL 138
Cdd:cd16227  237 LFASADDDHDDRLSFDEIL 255

EF-hand, calcium binding motif, found in calumenin, reticulocalbin-1 (RCN-1), reticulocalbin-3 (RCN-3), and similar proteins; The family corresponds to a group of six EF-hand Ca2+-binding proteins, including calumenin (also known as crocalbin or CBP-50), reticulocalbin-1 (RCN-1), reticulocalbin-3 (RCN-3), and similar proteins. Calumenin is an endo/sarcoplasmic reticulum (ER/SR) resident low-affinity Ca2+-binding protein that contains six EF-hand domains and a C-terminal SR retention signal His-Asp-Glu-Phe (HDEF) tetrapeptide. It functions as a novel regulator of SERCA2, and its expressional changes are tightly coupled with Ca2+-cycling of cardiomyocytes. It is also broadly involved in haemostasis and in the pathophysiology of thrombosis. Moreover, the extracellular calumenin acts as a suppressor of cell migration and tumor metastasis. RCN-1 is an endoplasmic reticulum resident Ca2+-binding protein with a carboxyl-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide signal. It acts as a potential negative regulator of B-RAF activation and can negatively modulate cardiomyocyte hypertrophy by inhibition of the mitogen-activated protein kinase signalling cascade. It also plays a key role in the development of doxorubicin-associated resistance. RCN-3 is a putative six EF-hand Ca2+-binding protein that contains five RXXR (X is any amino acid) motifs and a C-terminal ER retrieval signal HDEL tetrapeptide. The RXXR motif represents the target sequence of subtilisin-like proprotein convertases (SPCs). RCN-3 is specifically bound to the paired basic amino-acid-cleaving enzyme-4 (PACE4) precursor protein and plays an important role in the biosynthesis of PACE4.

Pssm-ID: 320024 [Multi-domain] Cd Length: 264 Bit Score: 43.34 E-value: 1.34e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   9 FDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMVRQMKEDAK-GKSEEELAEC--- 84
Cdd:cd16226   41 VDKIDKNGDGFVTEEELKDWIKYVQKKYIREDVDRQWKEYDPNKDGKLSWEEYKKATYGFLDDEEEdDDLHESYKKMirr 120

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 768018237  85 ----FRIFDRNADGYIDPEELAE-IFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMM 141
Cdd:cd16226  121 derrWKAADQDGDGKLTKEEFTAfLHPEEFPHMRDIVVQETLEDIDKNKDGFISLEEYIGDM 182

EF-hand, calcium binding motif, found in calumenin, reticulocalbin-1 (RCN-1), reticulocalbin-3 (RCN-3), and similar proteins; The family corresponds to a group of six EF-hand Ca2+-binding proteins, including calumenin (also known as crocalbin or CBP-50), reticulocalbin-1 (RCN-1), reticulocalbin-3 (RCN-3), and similar proteins. Calumenin is an endo/sarcoplasmic reticulum (ER/SR) resident low-affinity Ca2+-binding protein that contains six EF-hand domains and a C-terminal SR retention signal His-Asp-Glu-Phe (HDEF) tetrapeptide. It functions as a novel regulator of SERCA2, and its expressional changes are tightly coupled with Ca2+-cycling of cardiomyocytes. It is also broadly involved in haemostasis and in the pathophysiology of thrombosis. Moreover, the extracellular calumenin acts as a suppressor of cell migration and tumor metastasis. RCN-1 is an endoplasmic reticulum resident Ca2+-binding protein with a carboxyl-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide signal. It acts as a potential negative regulator of B-RAF activation and can negatively modulate cardiomyocyte hypertrophy by inhibition of the mitogen-activated protein kinase signalling cascade. It also plays a key role in the development of doxorubicin-associated resistance. RCN-3 is a putative six EF-hand Ca2+-binding protein that contains five RXXR (X is any amino acid) motifs and a C-terminal ER retrieval signal HDEL tetrapeptide. The RXXR motif represents the target sequence of subtilisin-like proprotein convertases (SPCs). RCN-3 is specifically bound to the paired basic amino-acid-cleaving enzyme-4 (PACE4) precursor protein and plays an important role in the biosynthesis of PACE4.

Pssm-ID: 320024 [Multi-domain] Cd Length: 264 Bit Score: 42.96 E-value: 1.66e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  45 IEEVDEDGSGTIDFEEFLVMMVRQ---MKEDAKGKSEEELAECFRifDRNADGYIDPEELAEIFRASGEHVTDEEIESLM 121
Cdd:cd16226  162 LEDIDKNKDGFISLEEYIGDMYRDddeEEDPDWVKSEREQFKEFR--DKNKDGKMDREEVKDWILPEDYDHAEAEAKHLI 239

                         90
                 ....*....|....*..
gi 768018237 122 KDGDKNNDGRIDFDEFL 138
Cdd:cd16226  240 YEADDDKDGKLTKEEIL 256

Eps15 homology domain; found in proteins implicated in endocytosis, vesicle transport, and signal transduction. The alignment contains a pair of EF-hand motifs, typically one of them is canonical and binds to Ca2+, while the other may not bind to Ca2+. A hydrophobic binding pocket is formed by residues from both EF-hand motifs. The EH domain binds to proteins containing NPF (class I), [WF]W or SWG (class II), or H[TS]F (class III) sequence motifs.

Pssm-ID: 238009 [Multi-domain] Cd Length: 67 Bit Score: 39.13 E-value: 4.20e-05

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 768018237  83 ECFRIFDRNADGYIDPEELAEIFRASGEHVTD-EEIESLMkdgDKNNDGRIDFDEF 137
Cdd:cd00052    3 QIFRSLDPDGDGLISGDEARPFLGKSGLPRSVlAQIWDLA---DTDKDGKLDKEEF 55

EF-hand, calcium binding motif, found in uncharacterized calglandulin-like proteins; The family corresponds to a group of uncharacterized calglandulin-like proteins. Although their biological function remain unclear, they show high sequence similarity with human calglandulin-like protein GAGLP, which is an ortholog of calglandulin from the venom glands of Bothrops insularis snake. Both GAGLP and calglandulin are putative Ca2+-binding proteins with four EF-hand motifs. However, members in this family contain only three EF-hand motifs. In this point, they may belong to the parvalbumin-like EF-hand family, which is characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix).

Pssm-ID: 319995 [Multi-domain] Cd Length: 106 Bit Score: 40.21 E-value: 4.28e-05

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 768018237   6 KAAFDMFDADGGGDISVKE----LGTVMRMLGQTP-TKEELDAIIEEVDEDGSGTIDFEEFLVM 64
Cdd:cd16252   40 RKAFQMLDKDKSGFIEWNEikyiLSTVPSSMPVAPlSDEEAEAMIQAADTDGDGRIDFQEFSDM 103

EF-hand, calcium binding motif, found in CREC-EF hand family; The CREC (Cab45/reticulocalbin/ERC45/calumenin)-EF hand family contains a group of six EF-hand, low-affinity Ca2+-binding proteins, including reticulocalbin (RCN-1), ER Ca2+-binding protein of 55 kDa (ERC-55, also known as TCBP-49 or E6BP), reticulocalbin-3 (RCN-3), Ca2+-binding protein of 45 kDa (Cab45 and its splice variant Cab45b), and calumenin ( also known as crocalbin or CBP-50). The proteins are not only localized in various parts of the secretory pathway, but also found in the cytosolic compartment and at the cell surface. They interact with different ligands or proteins and have been implicated in the secretory process, chaperone activity, signal transduction as well as in a large variety of disease processes.

Pssm-ID: 320021 [Multi-domain] Cd Length: 267 Bit Score: 41.27 E-value: 7.29e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   6 KAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMV-----RQMKEDAKGKSEEE 80
Cdd:cd15899   38 GVIVSKMDVDKDGFISAKELHSWILESFKRHAMEESKEQFRAVDPDEDGHVSWDEYKNDTYgsvgdDEENVADNIKEDEE 117

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 768018237  81 LAEC-------FRIFDRNADGYIDPEE-LAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMMEGVQ 145
Cdd:cd15899  118 YKKLllkdkkrFEAADQDGDLILTLEEfLAFLHPEESPYMLDFVIKETLEDLDKNGDGFISLEEFISDPYSAD 190

phosphatidylserine decarboxylase

Pssm-ID: 215520 [Multi-domain] Cd Length: 644 Bit Score: 41.38 E-value: 8.35e-05

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 768018237  87 IFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDE 136
Cdd:PLN02964 187 IVDYDEDGQLSFSEFSDLIKAFGNLVAANKKEELFKAADLNGDGVVTIDE 236

EF-hand domain pair;

Pssm-ID: 463900 [Multi-domain] Cd Length: 67 Bit Score: 38.00 E-value: 1.25e-04

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 768018237   46 EEVDEDGSGTIDFEEFLVMMvrQMKEDAKGKSEEELAECFRIFDRNADGYIDPEELAEIFR 106
Cdd:pfam13499   9 KLLDSDGDGYLDVEELKKLL--RKLEEGEPLSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

N-terminal domain of Myosin essential light chain ELC; ELC is part of the apicomplexan membrane-associated protein complex called the glideosome, which is essential for parasite motility. The glideosome is composed of six proteins: myosin A (MyoA), essential light chain ELC, myosin light chain MLC1 (also called MTIP), and the glideosome-associated proteins GAP40, GAP45, and GAP50. MyoA is a Class XIV myosin implicated in gliding motility, as well as host cell and tissue invasion by parasites. ELC binds to the MyoA neck region adjacent to the MLC1-binding site, and both myosin light chains co-located to the glideosome. Although ELCs bind to a conserved MyoA sequence, P. falciparum ELC adopts a distinct structure in the free and MyoA-bound state. Therefore ELCs enhance MyoA performance by inducing alpha helical structure formation in MyoA and thus stiffening its lever arm. It has been shown that disruption of MyoA, MLC1, or ELC have dramatic effects on parasite motility but do not affect parasite shape or replication. The ELC N-terminal domain is part of the EF-hand calcium binding motif superfamily. Calcium binding has no effect on the structure of ELCs.

Pssm-ID: 439385 [Multi-domain] Cd Length: 66 Bit Score: 37.71 E-value: 1.47e-04

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 768018237  77 SEEELAECFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESL 120
Cdd:cd22949    1 MEEKFREAFILFDRDGDGELTMYEAVLAMRSCGIPLTNDEKDAL 44

Eps15 homology domain; found in proteins implicated in endocytosis, vesicle transport, and signal transduction. The alignment contains a pair of EF-hand motifs, typically one of them is canonical and binds to Ca2+, while the other may not bind to Ca2+. A hydrophobic binding pocket is formed by residues from both EF-hand motifs. The EH domain binds to proteins containing NPF (class I), [WF]W or SWG (class II), or H[TS]F (class III) sequence motifs.

Pssm-ID: 238009 [Multi-domain] Cd Length: 67 Bit Score: 37.58 E-value: 1.77e-04

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 768018237   5 FKAAFDMFDADGGGDISVKELGTVMRMLGqTPtKEELDAIIEEVDEDGSGTIDFEEFLVMM 65
Cdd:cd00052    1 YDQIFRSLDPDGDGLISGDEARPFLGKSG-LP-RSVLAQIWDLADTDKDGKLDKEEFAIAM 59

Eps15 homology domain; Pair of EF hand motifs that recognise proteins containing Asn-Pro-Phe (NPF) sequences.

Pssm-ID: 197477 [Multi-domain] Cd Length: 96 Bit Score: 38.41 E-value: 1.77e-04

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 768018237    77 SEEELA---ECFRIFDRNADGYIDPEELAEIFRASGehVTDEEIESLMKDGDKNNDGRIDFDEF 137
Cdd:smart00027   5 SPEDKAkyeQIFRSLDKNQDGTVTGAQAKPILLKSG--LPQTLLAKIWNLADIDNDGELDKDEF 66

EF-hand, calcium binding motif, found in calumenin, reticulocalbin-1 (RCN-1), reticulocalbin-3 (RCN-3), and similar proteins; The family corresponds to a group of six EF-hand Ca2+-binding proteins, including calumenin (also known as crocalbin or CBP-50), reticulocalbin-1 (RCN-1), reticulocalbin-3 (RCN-3), and similar proteins. Calumenin is an endo/sarcoplasmic reticulum (ER/SR) resident low-affinity Ca2+-binding protein that contains six EF-hand domains and a C-terminal SR retention signal His-Asp-Glu-Phe (HDEF) tetrapeptide. It functions as a novel regulator of SERCA2, and its expressional changes are tightly coupled with Ca2+-cycling of cardiomyocytes. It is also broadly involved in haemostasis and in the pathophysiology of thrombosis. Moreover, the extracellular calumenin acts as a suppressor of cell migration and tumor metastasis. RCN-1 is an endoplasmic reticulum resident Ca2+-binding protein with a carboxyl-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide signal. It acts as a potential negative regulator of B-RAF activation and can negatively modulate cardiomyocyte hypertrophy by inhibition of the mitogen-activated protein kinase signalling cascade. It also plays a key role in the development of doxorubicin-associated resistance. RCN-3 is a putative six EF-hand Ca2+-binding protein that contains five RXXR (X is any amino acid) motifs and a C-terminal ER retrieval signal HDEL tetrapeptide. The RXXR motif represents the target sequence of subtilisin-like proprotein convertases (SPCs). RCN-3 is specifically bound to the paired basic amino-acid-cleaving enzyme-4 (PACE4) precursor protein and plays an important role in the biosynthesis of PACE4.

Pssm-ID: 320024 [Multi-domain] Cd Length: 264 Bit Score: 39.87 E-value: 1.85e-04

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 768018237  77 SEEELAECFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMMEG 143
Cdd:cd16226   33 SKERLGIIVDKIDKNGDGFVTEEELKDWIKYVQKKYIREDVDRQWKEYDPNKDGKLSWEEYKKATYG 99

EF-hand, calcium binding motif, found in Drosophila melanogaster calbindin-32 (CBN) and similar proteins; CBN, the product of the cbn gene, is a Drosophila homolog to vertebrate neuronal six EF-hand calcium binding proteins. It is expressed through most of ontogenesis with a selective distribution in the nervous system and in a few small adult thoracic muscles. Its precise biological role remains unclear. CBN contains six EF-hand motifs, but some of them may not bind calcium ions due to the lack of key residues.

Pssm-ID: 320079 [Multi-domain] Cd Length: 261 Bit Score: 40.09 E-value: 1.85e-04

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   4 EFKAAFDMFDADGGGDISVKELGTVMRML---GQTPTKEELDAIIEEV-------DEDGSGTIDFEEFLVMM-------V 66
Cdd:cd16179   96 EFMKVWREYDKDNSGYIEADELKNFLKHLlkeAKRDNDVSEDKLIEYTdtilqlfDRNKDGKLQLSEMARLLpvkenflC 175

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  67 RQMKEDAKGKSEEELAECFRIFDRNADGYIDPEELA----EIFRASGEHVTDEEI----ESLMKDGDKNNDGRIDFDEfL 138
Cdd:cd16179  176 RPIFKGAGKLTREDIDRVFALYDRDNNGTIENEELTgflkDLLELVQEDYDEQDLeefkEIILRGWDFNNDGKISRKE-L 254


                 ...
gi 768018237 139 KMM 141
Cdd:cd16179  255 TML 257

EF-hand, calcium binding motif; EF-hands are calcium-binding motifs that occur at least in pairs. Links between disease states and genes encoding EF-hands, particularly the S100 subclass, are emerging. Each motif consists of a 12 residue loop flanked on either side by a 12 residue alpha-helix. EF-hands undergo a conformational change unpon binding calcium ions.

Pssm-ID: 197492 [Multi-domain] Cd Length: 29 Bit Score: 36.20 E-value: 3.10e-04

                           10        20
                   ....*....|....*....|....*.
gi 768018237    40 ELDAIIEEVDEDGSGTIDFEEFLVMM 65
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLL 26

EF-hand motif found in phosphoinositide phospholipase C delta (PI-PLC-delta); PI-PLC-delta isozymes represent a class of metazoan PI-PLCs that are some of the most sensitive to calcium among all PLCs. Their activation is modulated by intracellular calcium ion concentration, phospholipids, polyamines, and other proteins, such as RhoAGAP. Like other PI-PLC isozymes, PI-PLC-delta isozymes contain a core set of domains, including an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core, and a single C-terminal C2 domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. There are three PI-PLC-delta isozymes (1, 3 and 4). PI-PLC-delta1 is relatively well characterized. It is activated by high calcium levels generated by other PI-PLC family members, and therefore functions as a calcium amplifier within the cell. Different PI-PLC-delta isozymes have different tissue distribution and different subcellular locations. PI-PLC-delta1 is mostly a cytoplasmic protein, PI-PLC-delta3 is located in the membrane, and PI-PLC-delta4 is predominantly detected in the cell nucleus. PI-PLC-delta isozymes is evolutionarily conserved even in non-mammalian species, such as yeast, slime molds and plants.

Pssm-ID: 320032 [Multi-domain] Cd Length: 140 Bit Score: 38.36 E-value: 3.43e-04

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 768018237  81 LAECFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLK 139
Cdd:cd16202    2 LKDQFRKADKNGDGKLSFKECKKLLKKLNVKVDKDYAKKLFQEADTSGEDVLDEEEFVQ 60

EF-hand, calcium binding motif, found in the hexa-EF hand proteins family; The hexa-EF hand proteins family, also named the calbindin sub-family, contains a group of six EF-hand Ca2+-binding proteins, including calretinin (CR, also termed 29 kDa calbindin), calbindin D28K (CB, also termed vitamin D-dependent calcium-binding protein, avian-type), and secretagogin (SCGN). CR is a cytosolic hexa-EF-hand calcium-binding protein predominantly expressed in a variety of normal and tumorigenic t-specific neurons of the central and peripheral nervous system. It is a multifunctional protein implicated in many biological processes, including cell proliferation, differentiation, and cell death. CB is highly expressed in brain tissue. It is a strong calcium-binding and buffering protein responsible for preventing a neuronal death as well as maintaining and controlling calcium homeostasis. SCGN is a six EF-hand calcium-binding protein expressed in neuroendocrine, pancreatic endocrine and retinal cells. It plays a crucial role in cell apoptosis, receptor signaling and differentiation. It is also involved in vesicle secretion through binding to various proteins, including interacts with SNAP25, SNAP23, DOC2alpha, ARFGAP2, rootletin, KIF5B, beta-tubulin, DDAH-2, ATP-synthase and myeloid leukemia factor 2. SCGN functions as a Ca2+ sensor/coincidence detector modulating vesicular exocytosis of neurotransmitters, neuropeptides or hormones. Although the family members share a significant amount of secondary sequence homology, they display altered structural and biochemical characteristics, and operate in distinct fashions. CB contains six EF-hand motifs in a single globular domain, where EF-hands 1, 3, 4, 5 bind four calcium ions. CR contains six EF-hand motifs within two independent domains, CR I-II and CR III-VI. They harbor two and four EF-hand motifs, respectively. The first 5 EF-hand motifs are capable of binding calcium ions, while the EF-hand 6 is inactive. SCGN consists of the three globular domains each of which contains a pair of EF-hand motifs. Human SCGN simultaneously binds four calcium ions through its EF-hands 3, 4, 5 and 6 in one high affinity and three low affinity calcium-binding sites. In contrast, SCGNs in other lower eukaryotes, such as D. rerio, X. laevis, M. domestica, G. gallus, O. anatinus, are fully competent in terms of six calcium-binding.

Pssm-ID: 320075 [Multi-domain] Cd Length: 254 Bit Score: 38.87 E-value: 3.97e-04

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   6 KAAFDMFDADGGGDISVKELgtvMRML--------------GQTPTKEELDAIIEEVDEDGSGTIDFEEFLV----MMVR 67
Cdd:cd15902  137 KLILKEFDANKDGKLELDEM---AKLLpvqenfllkfqilgAMDLTKEDFEKVFEHYDKDNNGVIEGNELDAllkdLLEK 213

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 768018237  68 QMKEDAKGKSEEELAECFRIFDRNADGYIDPEELAEIFRAS 108
Cdd:cd15902  214 NKADIDKPDLENFRDAILRACDKNKDGKIQKTELALFLSAK 254

N-terminal domain of Myosin essential light chain ELC; ELC is part of the apicomplexan membrane-associated protein complex called the glideosome, which is essential for parasite motility. The glideosome is composed of six proteins: myosin A (MyoA), essential light chain ELC, myosin light chain MLC1 (also called MTIP), and the glideosome-associated proteins GAP40, GAP45, and GAP50. MyoA is a Class XIV myosin implicated in gliding motility, as well as host cell and tissue invasion by parasites. ELC binds to the MyoA neck region adjacent to the MLC1-binding site, and both myosin light chains co-located to the glideosome. Although ELCs bind to a conserved MyoA sequence, P. falciparum ELC adopts a distinct structure in the free and MyoA-bound state. Therefore ELCs enhance MyoA performance by inducing alpha helical structure formation in MyoA and thus stiffening its lever arm. It has been shown that disruption of MyoA, MLC1, or ELC have dramatic effects on parasite motility but do not affect parasite shape or replication. The ELC N-terminal domain is part of the EF-hand calcium binding motif superfamily. Calcium binding has no effect on the structure of ELCs.

Pssm-ID: 439385 [Multi-domain] Cd Length: 66 Bit Score: 36.56 E-value: 4.10e-04

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 768018237   1 MIAEFKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDgsgtiDFEEFL 62
Cdd:cd22949    1 MEEKFREAFILFDRDGDGELTMYEAVLAMRSCGIPLTNDEKDALPASMNWD-----QFENWA 57

Penta-EF hand, calcium binding motifs, found in sorcin; Sorcin, also termed 22 kDa Ca2+-binding protein, CP-22, or V19, is a soluble resistance-related calcium-binding protein that is expressed in normal mammalian tissues, such as the liver, lungs and heart. The up-regulation of sorcin is correlated with a number of cancer types, including colorectal, gastric and breast cancer. It may represent a therapeutic target for reversing tumor multidrug resistance (MDR). Sorcin participates in the regulation of calcium homeostasis in cells and is necessary for the activation of mitosis and cytokinesis. It enhances metastasis and promotes epithelial-to-mesenchymal transition of colorectal cancer. Moreover, sorcin has been implicated in the regulation of intracellular Ca2+ cycling and cardiac excitation-contraction coupling. It displays the anti-apoptotic properties via the modulation of mitochondrial Ca2+ handling in cardiac myocytes. It can target and activate the sarcolemmal Na+/Ca2+ exchanger (NCX1) in cardiac muscle. Meanwhile, sorcin modulates cardiac L-type Ca2+ current by functional interaction with the alpha1C subunit. It also associates with calcium/calmodulin-dependent protein kinase IIdeltaC (CaMKIIdelta(C)) and further modulates ryanodine receptor (RyR) function in cardiac myocytes. Furthermore, sorcin may act as a Ca2+ sensor for glucose-induced nuclear translocation and the activation of carbohydrate-responsive element-binding protein (ChREBP)-dependent genes. As a mitochondrial chaperone TRAP1 interactor, sorcin involves in mitochondrial metabolism through the TRAP1 pathway. In addition, sorcin may regulate the inhibition of type I interferon response in cells through interacting with foot-and-mouth disease virus (FMDV) VP1. Sorcin contains a flexible glycine and proline-rich N-terminal extension and five EF-hand motifs that associate with membranes in a calcium-dependent manner. It may harbor three potential Ca2+ binding sites through its EF1, EF2 and EF3 hands. However, binding of only two Ca2+/monomer suffices to trigger the conformational change that exposes hydrophobic regions and leads to interaction with the respective targets. Sorcin forms homodimers through the association of the unpaired EF5 hand. Among the PEF proteins, sorcin is unique in that it contains potential phosphorylation sites by cAMP-dependent protein kinase (PKA), and it can form a tetramer at slightly acid pH values although remaining a stable dimer at neutral pH.

Pssm-ID: 320062 [Multi-domain] Cd Length: 165 Bit Score: 37.96 E-value: 5.35e-04

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  44 IIEEVDEDGSGTIDFEEF--LVMMVRQMKEDakgkseeelaecFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLM 121
Cdd:cd16187   45 MISMLDRDMSGTMGFNEFkeLWAVLNGWRQH------------FISFDSDRSGTVDPQELQKALTTMGFRLSPQAVNSIA 112

                         90
                 ....*....|....*..
gi 768018237 122 KDGDKNndGRIDFDEFL 138
Cdd:cd16187  113 KRYSTN--GKITFDDYI 127

EF-hand motif found in phosphoinositide phospholipase C delta (PI-PLC-delta); PI-PLC-delta isozymes represent a class of metazoan PI-PLCs that are some of the most sensitive to calcium among all PLCs. Their activation is modulated by intracellular calcium ion concentration, phospholipids, polyamines, and other proteins, such as RhoAGAP. Like other PI-PLC isozymes, PI-PLC-delta isozymes contain a core set of domains, including an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core, and a single C-terminal C2 domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. There are three PI-PLC-delta isozymes (1, 3 and 4). PI-PLC-delta1 is relatively well characterized. It is activated by high calcium levels generated by other PI-PLC family members, and therefore functions as a calcium amplifier within the cell. Different PI-PLC-delta isozymes have different tissue distribution and different subcellular locations. PI-PLC-delta1 is mostly a cytoplasmic protein, PI-PLC-delta3 is located in the membrane, and PI-PLC-delta4 is predominantly detected in the cell nucleus. PI-PLC-delta isozymes is evolutionarily conserved even in non-mammalian species, such as yeast, slime molds and plants.

Pssm-ID: 320032 [Multi-domain] Cd Length: 140 Bit Score: 37.59 E-value: 5.39e-04

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   6 KAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMVRQMKEDakgkseeELAECF 85
Cdd:cd16202    3 KDQFRKADKNGDGKLSFKECKKLLKKLNVKVDKDYAKKLFQEADTSGEDVLDEEEFVQFYNRLTKRP-------EIEELF 75

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 768018237  86 RIFDRNaDGYIDPEELAEIFRASGE--HVTDEEIESLMKDGDKNNDGRID----FDEFLKMMEG 143
Cdd:cd16202   76 KKYSGD-DEALTVEELRRFLQEEQKvkDVTLEWAEQLIETYEPSEDLKAQglmsLDGFTLFLLS 138

EF-hand, calcium binding motif, found in reticulocalbin-3 (RCN-3); RCN-3, also termed EF-hand calcium-binding protein RLP49, is a putative six EF-hand Ca2+-binding protein that contains five RXXR (X is any amino acid) motifs and a C-terminal ER retrieval signal His-Asp-Glu-Leu (HDEL) tetrapeptide. The RXXR motif represents the target sequence of subtilisin-like proprotein convertases (SPCs). RCN-3 is specifically bound to the paired basic amino-acid-cleaving enzyme-4 (PACE4) precursor protein and plays an important role in the biosynthesis of PACE4.

Pssm-ID: 320028 [Multi-domain] Cd Length: 268 Bit Score: 38.42 E-value: 5.49e-04

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   1 MIAEFKAAFDMFDADGGGDISVKELGTV--------MRMLGQTPTkeeldaiIEEVDEDGSGTIDFEEFLVMMVRQMKED 72
Cdd:cd16230  121 MLARDERRFRVADQDGDSMATREELTAFlhpeefphMRDIVVAET-------LEDLDKNKDGYVQVEEYIADLYSGEPGE 193

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 768018237  73 AKGKSEEELAECFRIF-DRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFL 138
Cdd:cd16230  194 EEPAWVQTERQQFRQFrDLNKDGRLDGSEVGHWVLPPSQDQPLVEANHLLHESDTDKDGRLSKAEIL 260

EF-hand domain;

Pssm-ID: 463869 [Multi-domain] Cd Length: 30 Bit Score: 35.23 E-value: 5.84e-04

                          10        20        30
                  ....*....|....*....|....*....|
gi 768018237   80 ELAECFRIFDRNADGYIDPEELAEIFRASG 109
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSLG 30

EF-hand, extracellular calcium-binding (EC) motif, found in secreted protein acidic and rich in cysteine (SPARC)-like proteins; The SPARC protein family represents a diverse group of proteins that share a follistatin-like (FS) domain and an extracellular calcium-binding (EC) domain with two EF-hand motifs. It includes SPARC (for secreted protein acidic and rich in cysteine, also termed osteonectin/ON, or basement-membrane protein 40/BM-40), SPARC-like protein 1 (for secreted protein, acidic and rich in cysteines-like 1/ SPARCL1, also termed high endothelial venule protein/Hevi, or MAST 9, or SC-1, or RAGS-1, or QR1, or ECM 2), testicans 1, 2, and 3 (also termed SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycans, or SPOCK), secreted modular calcium-binding protein SMOC-1 (also termed SPARC-related modular calcium-binding protein 1) and SMOC-2 (also termed SPARC-related modular calcium-binding protein 2, or smooth muscle-associated protein 2/SMAP-2), follistatin-related protein 1 (FRP-1, also termed follistatin-like protein 1/fstl-1, TSC-36/Flik, TGF-beta inducible protein). The SPARC proteins have been implicated in modulating cell interaction with the extracellular milieu, including regulation of extracellular matrix assembly and deposition, counter-adhesion, effects on extracellular protease activity, and modulation of growth factor/cytokine signaling pathways, as well as in development and disease.

Pssm-ID: 320009 Cd Length: 107 Bit Score: 36.97 E-value: 5.99e-04

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 768018237  85 FRIFDRNADGYIDPEELAEIFRASG--EHVTDEEIESLmkdgDKNNDGRIDFDEFLK 139
Cdd:cd00252   51 FDNLDNNKDGKLDKRELAPFRAPLMplEHCARGFFESC----DLNKDKKISLQEWLG 103

EF-hand, calcium binding motif, found in 45 kDa calcium-binding protein (Cab45); Cab45, also termed stromal cell-derived factor 4 (SDF-4), is a soluble, lumenal Golgi resident low-affinity Ca2+-binding protein that contains six copies of the EF-hand Ca2+-binding motif. It is required for secretory pathway calcium ATPase1 (SPCA1)-dependent Ca2+ import into the trans-Golgi network (TGN) and plays an essential role in Ca2+-dependent secretory cargo sorting at the TGN.

Pssm-ID: 320023 [Multi-domain] Cd Length: 278 Bit Score: 38.05 E-value: 8.78e-04

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  44 IIEEVDEDGSGTIDFEEFLVMMVRQMKEDAKGKSEEELAECFRIF----DRNADGYIDPEELAEIFRASGEHVTDEEIES 119
Cdd:cd16225  173 ILHDLDQDGDEKLTLDEFVSLPPGTVEEQQAEDDDEWKKERKKEFeeviDLNHDGKVTKEELEEYMDPRNERHALNEAKQ 252

                         90       100
                 ....*....|....*....|...
gi 768018237 120 LMKDGDKNNDGRIDFDEFLKMME 142
Cdd:cd16225  253 LIAVADENKDGKLSLEEILKNSD 275

S-100: S-100 domain, which represents the largest family within the superfamily of proteins carrying the Ca-binding EF-hand motif. Note that this S-100 hierarchy contains only S-100 EF-hand domains, other EF-hands have been modeled separately. S100 proteins are expressed exclusively in vertebrates, and are implicated in intracellular and extracellular regulatory activities. Intracellularly, S100 proteins act as Ca-signaling or Ca-buffering proteins. The most unusual characteristic of certain S100 proteins is their occurrence in extracellular space, where they act in a cytokine-like manner through RAGE, the receptor for advanced glycation products. Structural data suggest that many S100 members exist within cells as homo- or heterodimers and even oligomers; oligomerization contributes to their functional diversification. Upon binding calcium, most S100 proteins change conformation to a more open structure exposing a hydrophobic cleft. This hydrophobic surface represents the interaction site of S100 proteins with their target proteins. There is experimental evidence showing that many S100 proteins have multiple binding partners with diverse mode of interaction with different targets. In addition to S100 proteins (such as S100A1,-3,-4,-6,-7,-10,-11,and -13), this group includes the ''fused'' gene family, a group of calcium binding S100-related proteins. The ''fused'' gene family includes multifunctional epidermal differentiation proteins - profilaggrin, trichohyalin, repetin, hornerin, and cornulin; functionally these proteins are associated with keratin intermediate filaments and partially crosslinked to the cell envelope. These ''fused'' gene proteins contain N-terminal sequence with two Ca-binding EF-hands motif, which may be associated with calcium signaling in epidermal cells and autoprocessing in a calcium-dependent manner. In contrast to S100 proteins, "fused" gene family proteins contain an extraordinary high number of almost perfect peptide repeats with regular array of polar and charged residues similar to many known cell envelope proteins.

Pssm-ID: 238131 [Multi-domain] Cd Length: 88 Bit Score: 36.31 E-value: 9.47e-04

                         10        20        30
                 ....*....|....*....|....*....|.
gi 768018237 114 DEEIESLMKDGDKNNDGRIDFDEFLKMMEGV 144
Cdd:cd00213   50 PEAVDKIMKDLDVNKDGKVDFQEFLVLIGKL 80

EF-hand, calcium binding motif, found in parvalbumin-like EF-hand family; The family includes alpha- and beta-parvalbumins, and a group of uncharacterized calglandulin-like proteins. Parvalbumins are small, acidic, cytosolic EF-hand-containing Ca2+-buffer and Ca2+ transporter/shuttle proteins belonging to EF-hand superfamily. They are expressed by vertebrates in fast-twitch muscle cells, specific neurons of the central and peripheral nervous system, sensory cells of the mammalian auditory organ (Corti's cell), and some other cells, and characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. Thus, they may play an additional role in Mg2+ handling. Moreover, parvalbumins represent one of the major animal allergens. In metal-bound states, parvalbumins possess a rigid and stable tertiary structure and display strong allergenicity. In contrast, the metal-free parvalbumins are intrinsically disordered, and the loss of metal ions results in a conformational change that decreases their IgE binding capacity. Furthermore, parvalbumins have been widely used as a neuronal marker for a variety of functional brain systems. They also function as a Ca2+ shuttle transporting Ca2+ from troponin-C (TnC) to the sarcoplasmic reticulum (SR) Ca2+ pump during muscle relaxation. Thus they may facilitate myocardial relaxation and play important roles in cardiac diastolic dysfunction. Parvalbumins consists of alpha- and beta- sublineages, which can be distinguished on the basis of isoelectric point (pI > 5 for alpha; pI

Pssm-ID: 319994 [Multi-domain] Cd Length: 101 Bit Score: 36.36 E-value: 9.62e-04

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 768018237   3 AEFKAAFDMFDADGGGDISVKELGTVMRML---GQTPTKEELDAIIEEVDEDGSGTIDFEEFLVM 64
Cdd:cd16251   34 DQIKKVFQILDKDKSGFIEEEELKYILKGFsiaGRDLTDEETKALLAAGDTDGDGKIGVEEFATL 98

EF hand; The EF-hands can be divided into two classes: signalling proteins and buffering/transport proteins. The first group is the largest and includes the most well-known members of the family such as calmodulin, troponin C and S100B. These proteins typically undergo a calcium-dependent conformational change which opens a target binding site. The latter group is represented by calbindin D9k and do not undergo calcium dependent conformational changes.

Pssm-ID: 425435 [Multi-domain] Cd Length: 29 Bit Score: 34.68 E-value: 1.04e-03

                          10        20
                  ....*....|....*....|....*.
gi 768018237   40 ELDAIIEEVDEDGSGTIDFEEFLVMM 65
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELL 26

XopAW family type III secretion system calcium-binding effector;

Pssm-ID: 469301 [Multi-domain] Cd Length: 227 Bit Score: 37.74 E-value: 1.12e-03

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 768018237  74 KGKSEEELaecFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMME 142
Cdd:NF041410  25 SQQFQKQL---FAKLDSDGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDELAAAAP 90

EF-hand, calcium binding motif, found in calumenin; Calumenin, also termed crocalbin, or IEF SSP 9302, is an endo/sarcoplasmic reticulum (ER/SR) resident low-affinity Ca2+-binding protein that contains six EF-hand domains and a C-terminal SR retention signal His-Asp-Glu-Phe (HDEF) tetrapeptide. It is highly expressed in various brain regions. Thus it plays an important role in migration and differentiation of neurons, and/or in Ca2+ signaling between glial cells and neurons. Calumenin is involved in Ca2+ homeostasis through interacting with ryanodine receptor RyR2 and SERCA2. It acts as a novel regulator of SERCA2, and its expressional changes are tightly coupled with Ca2+-cycling of cardiomyocytes. Calumenin also forms a Ca2+-dependent complex with thrombospondin-1, which is broadly involved in haemostasis and thrombosis. Moreover, calumenin is a molecular chaperone that endogenously regulates the vitamin K-dependent gamma-carboxylation of several proteins, including blood coagulation factors (such as FII, FVII, FIX, FX, and proteins C, S and Z), cell survival factors (Gas6) and bone metabolism proteins (such as matrix Gla protein or MGP, osteocalcin and periostin), through targeting the gamma-glutamyl carboxylase. It also functions as a charged F508del-cystic fibrosis transmembrane regulator (CFTR) folding modulator, as well as a G551D-CFTR associated protein. Furthermore, the extracellular calumenin acts as a suppressor of cell migration and tumor metastasis. It binds to and stabilizes fibulin-1, and further inactivates extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling.

Pssm-ID: 320026 [Multi-domain] Cd Length: 263 Bit Score: 37.61 E-value: 1.35e-03

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  45 IEEVDEDGSGTIDFEEFLVMMVRQMKEDAKG---KSEEELAECFRifDRNADGYIDPEELAEIFRASGEHVTDEEIESLM 121
Cdd:cd16228  161 MEDIDKNGDGFIDLEEYIGDMYSQDGDADEPewvKTEREQFTEFR--DKNKDGKMDKEETKDWILPSDYDHAEAEARHLV 238

                         90
                 ....*....|....*..
gi 768018237 122 KDGDKNNDGRIDFDEFL 138
Cdd:cd16228  239 YESDQNKDGKLTKEEIV 255

Penta-EF hand, calcium binding motifs, found in calcium-dependent protease small subunit CAPNS1 and CAPNS2; CAPNS1, also termed calpain small subunit 1 (CSS1), or calcium-activated neutral proteinase small subunit (CANP small subunit), or calcium-dependent protease small subunit (CDPS), or calpain regulatory subunit, is a common 28-kDa regulatory calpain subunit encoded by the calpain small 1 (Capns1, also known as Capn4) gene. It acts as a binding partner to form a heterodimer with the 80 kDa calpain large catalytic subunit and is required in maintaining the activity of calpain. CAPNS1 plays a significant role in tumor progression of human cancer, and functions as a potential therapeutic target in human hepatocellular carcinoma (HCC), nasopharyngeal carcinoma (NPC), glioma, and clear cell renal cell carcinoma (ccRCC). It may be involved in regulating migration and cell survival through binding to the SH3 domain of Ras GTPase-activating protein (RasGAP). It may also modulate Akt/FoxO3A signaling and apoptosis through PP2A. CAPNS1 contains an N-terminal glycine rich domain and a C-terminal PEF-hand domain. CAPNS2, also termed calpain small subunit 2 (CSS2), is a novel tissue-specific 30 kDa calpain small subunit that lacks two oligo-Gly stretches characteristic of the N-terminal Gly-rich domain of CAPNS1. CAPNS2 acts as a chaperone for the calpain large subunit, and appears to be the functional equivalent of CAPNS1. However, CAPNS2 binds the large subunit much more weakly than CAPNS1 and it does not undergo the autolytic conversion typical of CAPNS1.

Pssm-ID: 320063 [Multi-domain] Cd Length: 169 Bit Score: 36.64 E-value: 1.91e-03

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  49 DEDGSGTIDFEEFLVMMVRQMKEDAkgkseeelaeCFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGdKNN 128
Cdd:cd16188   53 DSDTTGKLGFEEFKYLWNNIKKWQG----------IYKQFDTDRSGTIGSQELPGAFEAAGFHLNEQLYQMIIRRY-SDE 121

                         90
                 ....*....|
gi 768018237 129 DGRIDFDEFL 138
Cdd:cd16188  122 DGNMDFDNFI 131

EF-hand domain;

Pssm-ID: 463869 [Multi-domain] Cd Length: 30 Bit Score: 34.07 E-value: 2.02e-03

                          10        20        30
                  ....*....|....*....|....*....|
gi 768018237    4 EFKAAFDMFDADGGGDISVKELGTVMRMLG 33
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSLG 30

Penta-EF hand, calcium binding motifs, found in Drosophila melanogaster calpain-A (CalpA), calpain-B (CalpB), and similar proteins; The family contains two calpains that have been found in Drosophila, CalpA and CalpB. CalpA, also termed calcium-activated neutral proteinase A (CANP A), or calpain-A catalytic subunit, is a Drosophila calpain homolog specifically expressed in a few neurons in the central nervous system, in scattered endocrine cells in the midgut, and in blood cells. CalpB, also termed calcium-activated neutral proteinase B (CANP B), contains calpain-B catalytic subunit 1 and calpain-B catalytic subunit 2. Both CalpA and CalpB are closely related to that of vertebrate calpains, and they share similar domain architecture, which consists of four domains: the N-terminal domain I, the catalytic domain II carrying the three active site residues, Cys, His and Asn, the Ca2+-regulated phospholipid-binding domain III, and penta-EF-hand Ca2+-binding domain IV. Besides, CalpA and CalpB display some distinguishing structural features that are not found in mammalian typical calpains. CalpA harbors a 76 amino acid long hydrophobic stretch inserted in domain IV, which may be involved in membrane attachment of this enzyme. CalpB has an unusually long N-terminal tail of 224 amino acids, which belongs to the class of intrinsically unstructured proteins (IUP) and may become ordered upon binding to target protein(s). Moreover, they do not need small regulatory subunits for their catalytic activity, and their proteolytic function is not regulated by an intrinsic inhibitor as the Drosophila genome contains neither regulatory subunit nor calpastatin orthologs. As a result, they may exist as a monomer or perhaps as a homo- or heterodimer together with a second large subunit. Furthermore, both CalpA and CalpB are dispensable for viability and fertility and do not share vital functions during Drosophila development. Phosphatidylinositol 4,5-diphosphate, phosphatidylinositol 4-monophosphate, phosphatidylinositol, and phosphatidic acid can stimulate the activity and the rate of activation of CalpA, but not CalpB. Calpain A modulates Toll responses by limited Cactus/IkappaB proteolysis. CalpB directly interacts with talin, an important component of the focal adhesion complex, and functions as an important modulator in border cell migration within egg chambers, which may act via the digestion of talin. CalpB can be phosphorylated by cAMP-dependent protein kinase (protein kinase A, PKA; EC 2.7.11.11) at Ser240 and Ser845, as well as by mitogen-activated protein kinase (ERK1 and ERK2; EC 2.7.11.24) at Thr747. The activation of the ERK pathway by extracellular signals results in the phosphorylation and activation of calpain B. In Schneider cells (S2), calpain B was mainly in the cytoplasm and upon a rise in Ca2+ the enzyme adhered to intracellular membranes.

Pssm-ID: 320071 [Multi-domain] Cd Length: 167 Bit Score: 36.03 E-value: 2.45e-03

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  49 DEDGSGTIDFEEF--LVMMVRQMKedakgkseeelaECFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESL-MKDGD 125
Cdd:cd16196   51 DVDRSGKLGFEEFkkLWEDLRSWK------------RVFKLFDTDGSGSFSSFELRNALNSAGFRLSNATLNALvLRYSN 118

                         90
                 ....*....|....*.
gi 768018237 126 KnnDGRIDFDEFLKMM 141
Cdd:cd16196  119 K--DGRISFDDFIMCA 132

EF-hand, calcium binding motif; EF-hands are calcium-binding motifs that occur at least in pairs. Links between disease states and genes encoding EF-hands, particularly the S100 subclass, are emerging. Each motif consists of a 12 residue loop flanked on either side by a 12 residue alpha-helix. EF-hands undergo a conformational change unpon binding calcium ions.

Pssm-ID: 197492 [Multi-domain] Cd Length: 29 Bit Score: 33.51 E-value: 2.48e-03

                           10        20
                   ....*....|....*....|....*.
gi 768018237   116 EIESLMKDGDKNNDGRIDFDEFLKMM 141
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLL 26

EF-hand, calcium binding motif, found in 45 kDa calcium-binding protein (Cab45); Cab45, also termed stromal cell-derived factor 4 (SDF-4), is a soluble, lumenal Golgi resident low-affinity Ca2+-binding protein that contains six copies of the EF-hand Ca2+-binding motif. It is required for secretory pathway calcium ATPase1 (SPCA1)-dependent Ca2+ import into the trans-Golgi network (TGN) and plays an essential role in Ca2+-dependent secretory cargo sorting at the TGN.

Pssm-ID: 320023 [Multi-domain] Cd Length: 278 Bit Score: 36.12 E-value: 3.80e-03

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  51 DGSGTIDF--EEFLVMMVRQMKEDAKGKSEEELAECFRIFDRNADGYIDPEELAE-IFRASGEHVTD--EEIESLMKDGD 125
Cdd:cd16225    4 DGHLNKEFhkEVFLGNEKEEFEEDSEPKKRKKLKEIFKKVDVNTDGFLSAEELEDwIMEKTQEHFQEavEENEQIFKAVD 83

                         90
                 ....*....|..
gi 768018237 126 KNNDGRIDFDEF 137
Cdd:cd16225   84 TDKDGNVSWEEY 95

Penta-EF hand, calcium binding motifs, found in calpain-12 (CAPN12); CAPN12, also termed calcium-activated neutral proteinase 12 (CANP 12), is a calpain large subunit mainly expressed in the cortex of the hair follicle. It may affect apoptosis regulation. CAPN12 contains a short N-terminal anchor helix, followed by a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2+-binding penta-EF-hand (PEF) domain.

Pssm-ID: 320069 [Multi-domain] Cd Length: 169 Bit Score: 35.62 E-value: 4.12e-03

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  19 DISVKELGTVM-----RMLGQTPTKEELDA---IIEEVDEDGSGTIDFEEFlvmmvRQMKEDAKgkseeELAECFRIFDR 90
Cdd:cd16194   15 EINASELQKILsialeRAHTSKPREFGLRTcrqLIQCFDHGQNGKLALEEF-----QQLWGYLL-----EWQAIFTKFDE 84

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 768018237  91 NADGYIDPEELAEIFRASGEHVTDEEIESLMKDGdKNNDGRIDFDEFL 138
Cdd:cd16194   85 DTSGTMDSYELRLALNAAGFHLNNQLTETLTSRY-RDSRLRVDFESFL 131

EF-hand, calcium binding motif; EF-hands are calcium-binding motifs that occur at least in pairs. Links between disease states and genes encoding EF-hands, particularly the S100 subclass, are emerging. Each motif consists of a 12 residue loop flanked on either side by a 12 residue alpha-helix. EF-hands undergo a conformational change unpon binding calcium ions.

Pssm-ID: 197492 [Multi-domain] Cd Length: 29 Bit Score: 32.74 E-value: 4.73e-03

                           10        20
                   ....*....|....*....|....*...
gi 768018237    80 ELAECFRIFDRNADGYIDPEELAEIFRA 107
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKA 28

The penta-EF hand (PEF) family; The penta-EF hand (PEF) family contains a group of five EF-hand calcium-binding proteins, including several classical calpain large catalytic subunits (CAPN1, 2, 3, 8, 9, 11, 12, 13, 14), two calpain small subunits (CAPNS1 and CAPNS2), as well as non-calpain PEF proteins, ALG-2 (apoptosis-linked gene 2, also termed programmed cell death protein 6, PDCD6), peflin, sorcin, and grancalcin. Based on the sequence similarity of EF1 hand, ALG-2 and peflin have been classified into group I PEF proteins. Calcium-dependent protease calpain subfamily members, sorcin and grancalcin, are group II PEF proteins. Calpains (EC 3.4.22.17) are calcium-activated intracellular cysteine proteases that play important roles in the degradation or functional modulation in a variety of substrates. They have been implicated in a number of physiological processes such as cell cycle progression, remodeling of cytoskeletal-cell membrane attachments, signal transduction, gene expression and apoptosis. ALG-2 is a pro-apoptotic factor that forms a homodimer in the cell or a heterodimer with its closest paralog peflin through their EF5s. Peflin is a 30-kD PEF protein with a longer N-terminal hydrophobic domain than any other member of the PEF family, and it contains nine nonapeptide (A/PPGGPYGGP) repeats. It exists only as a heterodimer with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+. ALG-2 interacts with various proteins in a Ca2+-dependent manner. Sorcin (for soluble resistance-related calcium binding protein) is a soluble resistance-related calcium-binding protein that participates in the regulation of calcium homeostasis in cells. Grancalcin is a cytosolic Ca2+-binding protein specifically expressed in neutrophils and monocytes/macrophages. It plays a key role in leukocyte-specific functions that are responsible for host defense. Grancalcin can form a heterodimer together with sorcin. Members in this family contain five EF-hand motifs attached to an N-terminal region of variable length containing one or more short Gly/Pro-rich sequences. These proteins form homodimers or heterodimers through pairing between the 5th EF-hands from the two molecules. Unlike calmodulin, the PEF domains do not undergo major conformational changes upon binding Ca2+.

Pssm-ID: 320054 [Multi-domain] Cd Length: 165 Bit Score: 35.48 E-value: 4.91e-03

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237   2 IAEFKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDeDGSGTIDFEEFLVMMVRQmkedakgkseEEL 81
Cdd:cd15897   69 IKAWQEIFRTYDTDGSGTIDSNELRQALSGAGYRLSEQTYDIIIRRYD-RGRGNIDFDDFIQCCVRL----------QRL 137

                         90
                 ....*....|....*
gi 768018237  82 AECFRIFDRNADGYI 96
Cdd:cd15897  138 TDAFRRYDKDQDGQI 152

EF-hand, calcium binding motif, found in reticulocalbin-2 (RCN2) mainly from protostomes; This family corresponds to a group of uncharacterized RCN2-like proteins, which are mainly found in protostomes. Although their biological function remains unclear, they show high sequence similarity with RCN2 (also known as E6BP or TCBP-49), which is an endoplasmic reticulum resident low-affinity Ca2+-binding protein that has been implicated in immunity, redox homeostasis, cell cycle regulation and coagulation. Members in this family contain six copies of the EF-hand Ca2+-binding motif, but may lack a C-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide that is required for retention of RCN2 in the endoplasmic reticulum (ER).

Pssm-ID: 320025 [Multi-domain] Cd Length: 263 Bit Score: 35.76 E-value: 5.18e-03

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 768018237  77 SEEELAECFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLK 139
Cdd:cd16227   34 AKRRLAVLAKKMDLNDDGFIDRKELKAWILRSFKMLDEEEANERFEEADEDGDGKVTWEEYLA 96

EF hand; The EF-hands can be divided into two classes: signalling proteins and buffering/transport proteins. The first group is the largest and includes the most well-known members of the family such as calmodulin, troponin C and S100B. These proteins typically undergo a calcium-dependent conformational change which opens a target binding site. The latter group is represented by calbindin D9k and do not undergo calcium dependent conformational changes.

Pssm-ID: 425435 [Multi-domain] Cd Length: 29 Bit Score: 32.37 E-value: 6.34e-03

                          10        20
                  ....*....|....*....|....*..
gi 768018237  116 EIESLMKDGDKNNDGRIDFDEFLKMME 142
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLK 27

Penta-EF hand, calcium binding motifs, found in grancalcin; Grancalcin (GCA) is a cytosolic Ca2+-binding protein specifically expressed in neutrophils and monocytes/macrophages. It displays a Ca2+-dependent translocation to granules and plasma membrane upon neutrophil activation, suggesting roles in granule-membrane fusion and degranulation of neutrophils. It may also play a role in the regulation of vesicle/granule exocytosis through the reversible binding of secretory vesicles and plasma membranes upon the presence of calcium. Moreover, GCA is involved in inflammation, as well as in the process of adhesion of neutrophils to fibronectin. It plays a key role in leukocyte-specific functions that are responsible for host defense, and affects the function of integrin receptors on immune cells through binding to L-plastin in the absence of calcium. Furthermore, GCA can strongly interact with sorcin to form a heterodimer, and further modulate the function of sorcin. GCA exists as homodimers in solution. It contains five EF-hand motifs attached to an N-terminal region of an approximately 50 residue-long segment rich in glycines and prolines. GCA binds two Ca2+ ions through its EF1 and EF3 hands.

Pssm-ID: 320061 [Multi-domain] Cd Length: 165 Bit Score: 34.84 E-value: 6.84e-03

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768018237  44 IIEEVDEDGSGTIDFEEF--LVMMVRQMKEDakgkseeelaecFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLM 121
Cdd:cd16186   45 MIAMLDRDHTGKMGFNEFkeLWAALNAWKQN------------FMTVDQDRSGTVEPHELRQAIGAMGYRLSPQTLTTIV 112

                         90
                 ....*....|....*..
gi 768018237 122 KDGDKNndGRIDFDEFL 138
Cdd:cd16186  113 KRYSKN--GRIYFDDYV 127

Formin Homology 2 Domain; FH proteins control rearrangements of the actin cytoskeleton, especially in the context of cytokinesis and cell polarisation. Members of this family have been found to interact with Rho-GTPases, profilin and other actin-assoziated proteins. These interactions are mediated by the proline-rich FH1 domain, usually located in front of FH2 (but not listed in SMART). Despite this cytosolic function, vertebrate formins have been assigned functions within the nucleus. A set of Formin-Binding Proteins (FBPs) has been shown to bind FH1 with their WW domain.

Pssm-ID: 214697 [Multi-domain] Cd Length: 392 Bit Score: 35.40 E-value: 7.03e-03

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|
gi 768018237    18 GDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMVR 67
Cdd:smart00498 106 GDEDVLSVDLLEQLLKYAPTKEELKKLREYKEEDPEELARAEQFLLLISN 155

S-100: S-100 domain, which represents the largest family within the superfamily of proteins carrying the Ca-binding EF-hand motif. Note that this S-100 hierarchy contains only S-100 EF-hand domains, other EF-hands have been modeled separately. S100 proteins are expressed exclusively in vertebrates, and are implicated in intracellular and extracellular regulatory activities. Intracellularly, S100 proteins act as Ca-signaling or Ca-buffering proteins. The most unusual characteristic of certain S100 proteins is their occurrence in extracellular space, where they act in a cytokine-like manner through RAGE, the receptor for advanced glycation products. Structural data suggest that many S100 members exist within cells as homo- or heterodimers and even oligomers; oligomerization contributes to their functional diversification. Upon binding calcium, most S100 proteins change conformation to a more open structure exposing a hydrophobic cleft. This hydrophobic surface represents the interaction site of S100 proteins with their target proteins. There is experimental evidence showing that many S100 proteins have multiple binding partners with diverse mode of interaction with different targets. In addition to S100 proteins (such as S100A1,-3,-4,-6,-7,-10,-11,and -13), this group includes the ''fused'' gene family, a group of calcium binding S100-related proteins. The ''fused'' gene family includes multifunctional epidermal differentiation proteins - profilaggrin, trichohyalin, repetin, hornerin, and cornulin; functionally these proteins are associated with keratin intermediate filaments and partially crosslinked to the cell envelope. These ''fused'' gene proteins contain N-terminal sequence with two Ca-binding EF-hands motif, which may be associated with calcium signaling in epidermal cells and autoprocessing in a calcium-dependent manner. In contrast to S100 proteins, "fused" gene family proteins contain an extraordinary high number of almost perfect peptide repeats with regular array of polar and charged residues similar to many known cell envelope proteins.

Pssm-ID: 238131 [Multi-domain] Cd Length: 88 Bit Score: 33.62 E-value: 8.62e-03

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|...
gi 768018237  23 KELGTVMRMLGQTPTkeeLDAIIEEVDEDGSGTIDFEEFLVMM 65
Cdd:cd00213   38 TELPNFLKNQKDPEA---VDKIMKDLDVNKDGKVDFQEFLVLI 77