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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4506025   20 IKRLGKRFKKLDLDNSGSLSVEEFMSLPElqqnPLVQRVIDIFDTDGNGEVDFKEFIEGVSQfSVKGDKEQKLRFAFRIY 99
Cdd:COG5126   4 RRKLDRRFDLLDADGDGVLERDDFEALFR----RLWATLFSEADTDGDGRISREEFVAGMES-LFEATVEPFARAAFDLL 78

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 4506025  100 DMDKDGYISNGELFQVLKMMvgnNLKDTQLQQIVDKtiinADKDGDGRISFEEFCAVV 157
Cdd:COG5126  79 DTDGDGKISADEFRRLLTAL---GVSEEEADELFAR----LDTDGDGKISFEEFVAAV 129

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4506025   20 IKRLGKRFKKLDLDNSGSLSVEEFMSLPElqqnPLVQRVIDIFDTDGNGEVDFKEFIEGVSQfSVKGDKEQKLRFAFRIY 99
Cdd:COG5126   4 RRKLDRRFDLLDADGDGVLERDDFEALFR----RLWATLFSEADTDGDGRISREEFVAGMES-LFEATVEPFARAAFDLL 78

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 4506025  100 DMDKDGYISNGELFQVLKMMvgnNLKDTQLQQIVDKtiinADKDGDGRISFEEFCAVV 157
Cdd:COG5126  79 DTDGDGKISADEFRRLLTAL---GVSEEEADELFAR----LDTDGDGKISFEEFVAAV 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.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 4506025   91 KLRFAFRIYDMDKDGYISNGELFQVLKMmvgnnLKDTQLQQIVDKTIINADKDGDGRISFEEFCAVV 157
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKS-----LGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELM 62

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4506025    25 KRFKKLDLDNSGSLSVEEFMSLpeLQQNPLVQRVIDI------FDTDGNGEVDFKEFIEG------VSQFSVKGDKEQKL 92
Cdd:NF041410  31 QLFAKLDSDGDGSVSQDELSSA--LSSKSDDGSLIDLselfsdLDSDGDGSLSSDELAAAapppppPPDQAPSTELADDL 108

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 4506025    93 RFAFriyDMDKDGYISNGELfQVLKMMVGNNLKDTQLqqivdktiINA-DKDGDGRISFEEFCA 155
Cdd:NF041410 109 LSAL---DTDGDGSISSDEL-SAGLTSAGSSADSSQL--------FSAlDSDGDGSVSSDELAA 160

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4506025    23 LGKRFKKLDLDNSGSLSVEEFMSL-----PELQQNPLVQRVIDIF---DTDGNGEVDFKEFIEGVSQFSVKGDKEQklrf 94
Cdd:NF041410  65 LSELFSDLDSDGDGSLSSDELAAAappppPPPDQAPSTELADDLLsalDTDGDGSISSDELSAGLTSAGSSADSSQ---- 140

                         90
                 ....*....|....*...
gi 4506025    95 AFRIYDMDKDGYISNGEL 112
Cdd:NF041410 141 LFSALDSDGDGSVSSDEL 158

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4506025   20 IKRLGKRFKKLDLDNSGSLSVEEFMSLPElqqnPLVQRVIDIFDTDGNGEVDFKEFIEGVSQfSVKGDKEQKLRFAFRIY 99
Cdd:COG5126   4 RRKLDRRFDLLDADGDGVLERDDFEALFR----RLWATLFSEADTDGDGRISREEFVAGMES-LFEATVEPFARAAFDLL 78

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 4506025  100 DMDKDGYISNGELFQVLKMMvgnNLKDTQLQQIVDKtiinADKDGDGRISFEEFCAVV 157
Cdd:COG5126  79 DTDGDGKISADEFRRLLTAL---GVSEEEADELFAR----LDTDGDGKISFEEFVAAV 129

centrin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4506025    18 DEIKRLGKRFKKLDLDNSGSLSVEEF----MSLPELQQNPLVQRVIDIFDTDGNGEVDFKEFIEGVSQFSVKGDKEQKLR 93
Cdd:PTZ00183  14 DQKKEIREAFDLFDTDGSGTIDPKELkvamRSLGFEPKKEEIKQMIADVDKDGSGKIDFEEFLDIMTKKLGERDPREEIL 93

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 4506025    94 FAFRIYDMDKDGYISNGELFQVLKMMvGNNLKDTQLQQIVDKtiinADKDGDGRISFEEF 153
Cdd:PTZ00183  94 KAFRLFDDDKTGKISLKNLKRVAKEL-GETITDEELQEMIDE----ADRNGDGEISEEEF 148

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+.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4506025   27 FKKLDLDNSGSLSVEEfmslpeLQQ-----------NPLVQRVIDIFDTDGNGEVDFKEFIeGVSQFSvkgdkeQKLRFA 95
Cdd:cd16180   6 FQAVDRDRSGRISAKE------LQRalsngdwtpfsIETVRLMINMFDRDRSGTINFDEFV-GLWKYI------QDWRRL 72

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 4506025   96 FRIYDMDKDGYISNGELFQVLKMMvGNNLKDTQLQQIVDKTiinaDKDGDGRISFEEF---CAVVGGL 160
Cdd:cd16180  73 FRRFDRDRSGSIDFNELQNALSSF-GYRLSPQFVQLLVRKF----DRRRRGSISFDDFveaCVTLKRL 135

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).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4506025   25 KRFKKLDLDNSGSLSVEEFMSLpelqQNP---------LVQRVIDIFDTDGNGEVDFKEFI-EGVSQFSVKGDKEQKLRF 94
Cdd:cd16227 126 EMFEAADLNKDGKLDKTEFSAF----QHPeeyphmhpvLIEQTLRDKDKDNDGFISFQEFLgDRAGHEDKEWLLVEKDRF 201

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 4506025   95 AfRIYDMDKDGYISNGElfqVLKMMVGNNlkDTQLQQIVDKTIINADKDGDGRISFEE 152
Cdd:cd16227 202 D-EDYDKDGDGKLDGEE---ILSWLVPDN--EEIAEEEVDHLFASADDDHDDRLSFDE 253

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.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 4506025   25 KRFKKLDLDNSGSLSVEEFM----SLPELQQNPLVQRVIDIFDTDGNGEVDFKEFIEGVS 80
Cdd:cd00051   4 EAFRLFDKDGDGTISADELKaalkSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

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).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4506025   68 GEVDFKEFIEGVSQFSVKGDKEQKLRFAFRIYDMDKDGYISNGELFQVLKMMVGNNLKDTQLQQIVDKTIINADKDGDGR 147
Cdd:cd16252  15 GSFNYSKFFEYMQKFQTSEQQEEAIRKAFQMLDKDKSGFIEWNEIKYILSTVPSSMPVAPLSDEEAEAMIQAADTDGDGR 94

                        90
                ....*....|
gi 4506025  148 ISFEEFCAVV 157
Cdd:cd16252  95 IDFQEFSDMV 104

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4506025   22 RLGKRFKKLDLDNSGSLSVEEFMSLPELQQNP-----LVQRVIDIFDTDGNGEVDFKEFIEGV--------SQFSVKGDK 88
Cdd:cd15899 124 KDKKRFEAADQDGDLILTLEEFLAFLHPEESPymldfVIKETLEDLDKNGDGFISLEEFISDPysadeneeEPEWVKVEK 203

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 4506025   89 EQKLRFafriYDMDKDGYISNGELfqvLKMMVGNNlkDTQLQQIVDKTIINADKDGDGRISFEE 152
Cdd:cd15899 204 ERFVEL----RDKDKDGKLDGEEL---LSWVDPSN--QEIALEEAKHLIAESDENKDGKLSPEE 258

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 4506025     20 IKRLGKRFKKLDLDNSGSLSVEEFMSL--PELQQNPL----VQRVIDIFDTDGNGEVDFKEFIEGVS 80
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLlrKLEEGEPLsdeeVEELFKEFDLDKDGRISFEEFLELYS 67

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4506025   27 FKKLDLDNSGSLSVEEfmslpeLQQ----------NPLVQR-VIDIFDTDGNGEVDFKEFiEGVSQFSvkgdkeQKLRFA 95
Cdd:cd16183   6 FQRVDKDRSGQISATE------LQQalsngtwtpfNPETVRlMIGMFDRDNSGTINFQEF-AALWKYI------TDWQNC 72

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 4506025   96 FRIYDMDKDGYISNGELFQVLKMMvGNNLKDTQLQQIVDKTiinaDKDGDGRISFEEF--CAVV 157
Cdd:cd16183  73 FRSFDRDNSGNIDKNELKQALTSF-GYRLSDQFYDILVRKF----DRQGRGTIAFDDFiqCCVV 131

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4506025   68 GEVDFKEFIEGVSqfsVKGDKEQKLRFAFRIYDMDKDGYISNGELFQVLKMM--VGNNLKDTQLQQIvdktIINADKDGD 145
Cdd:cd16251  15 GSFNYKKFFEHVG---LKQKSEDQIKKVFQILDKDKSGFIEEEELKYILKGFsiAGRDLTDEETKAL----LAAGDTDGD 87

                        90
                ....*....|....
gi 4506025  146 GRISFEEFCAVVGG 159
Cdd:cd16251  88 GKIGVEEFATLVAG 101

serine/threonine protein phosphatase 2A regulatory subunit B" subunit gamma; Heterotrimeric serine/threonine protein phosphatase 2A (PP2A) consists of scaffolding (A), catalytic (C), and variable (B, B', and B") subunits. The variable subunits dictate subcellular localization and substrate specificity of the PP2A holoenzyme. This subfamily includes protein phosphatase subunit G5PR (also known as serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma, G4-1, G5pr, GDRM, SPGF36, or C14orf10) that is encoded by the PPP2R3C gene. It is involved in the control of the dynamic organization of the cortical cytoskeleton and plays an important role in the organization of interphase microtubule arrays in part through the regulation of nucleation geometry. G5PR is involved in the ontogeny of multiple organs, especially critical for testis development and spermatogenesis. PPP2R3C gene variants cause syndromic 46,XY gonadal dysgenesis and impaired spermatogenesis in humans, and thus is emerging as a potential therapeutic target for male infertility.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4506025    3 NEASYPLEMCSHFDADEIKRLGKRFKKLDLDNSGSLSVEEfmsLPELQQNPLVQRVID-IFDTDG--NGEVDFKEFIEGV 79
Cdd:cd21505 203 EELSEELQESNWFSAPSALRVYGQYLNLDKDHNGMLSKQE---LSRYGKGTLTSVFIDrVFQECLtyNGEMDYKTFLDFV 279

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 4506025   80 SQFSVKGDKeQKLRFAFRIYDMDKDGYISNGEL---FQ-VLKMMVGNNLKDTQLQQIVD 134
Cdd:cd21505 280 LAMENRKEP-QALQYFFRILDLKGQGYLTPFTLnyfFRaIQEKMKEHGQEPVSFEDVKD 337

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4506025   71 DFKEFIEGVSqfsVKGDKEQKLRFAFRIYDMDKDGYISNGELFQVLKMMV--GNNLKDTQLQQIVDKtiinADKDGDGRI 148
Cdd:cd16254  18 DYKKFFEMVG---LKKKSADDVKKVFHILDKDKSGFIEEDELKFVLKGFSpdGRDLSDKETKALLAA----GDKDGDGKI 90

                ....*....
gi 4506025  149 SFEEFCAVV 157
Cdd:cd16254  91 GIDEFATLV 99

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4506025   25 KRFKKLDLDNSGSLSVEE---FMSLPELQQNPLV---------QRVIDIFDTDGNGEVDFKEFIEGVS-------QFSVK 85
Cdd:cd15902  94 KIWRKYDTDGSGFIEAKElkgFLKDLLLKNKKHVsppkldeytKLILKEFDANKDGKLELDEMAKLLPvqenfllKFQIL 173

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 4506025   86 GDKEQK---LRFAFRIYDMDKDGYISNGELFQVLKMMVGNNLKDTQLQQIVD--KTIIN-ADKDGDGRISFEEFC 154
Cdd:cd15902 174 GAMDLTkedFEKVFEHYDKDNNGVIEGNELDALLKDLLEKNKADIDKPDLENfrDAILRaCDKNKDGKIQKTELA 248

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4506025   59 IDIFDTDGNGEVDFKEFIE---GVSQFsvkgdkeqklRFAFRIYDMDKDGYISNGELFQVLKMMvGNNLKDTQLQQIVDK 135
Cdd:cd16181  46 IAMLDRDHSGKMGFNEFKElwaALNQW----------KTTFMQYDRDRSGTVEPQELQQAIRSF-GYNLSPQALNVIVKR 114

                        90       100
                ....*....|....*....|...
gi 4506025  136 TIINadkdgdGRISFEEF--CAV 156
Cdd:cd16181 115 YSKN------GRITFDDFvaCAV 131

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+.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4506025   27 FKKLDLDNSGSLSVEEFMSLpeLQQ------NPLVQRVIDIFDTDGNGEVDFKEFIEGVsqFSVKGdkeqkLRFAFRIYD 100
Cdd:cd16180  73 FRRFDRDRSGSIDFNELQNA--LSSfgyrlsPQFVQLLVRKFDRRRRGSISFDDFVEAC--VTLKR-----LTDAFRKYD 143

                ....*..
gi 4506025  101 MDKDGYI 107
Cdd:cd16180 144 TNRTGYA 150

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

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 4506025      89 EQKLRFA--FRIYDMDKDGYISNGelfQVLKMMVGNNLKDTQLQQIVDKtiinADKDGDGRISFEEFCA 155
Cdd:smart00027   7 EDKAKYEqiFRSLDKNQDGTVTGA---QAKPILLKSGLPQTLLAKIWNL----ADIDNDGELDKDEFAL 68

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4506025   21 KRLGKRFKKLDLDNSGSLSVEEFMSLPELQQNPL----VQRVIDIFDTDGNGEVDFKEFIegVSQFSVKGDKEQ------ 90
Cdd:cd15899  35 RRLGVIVSKMDVDKDGFISAKELHSWILESFKRHameeSKEQFRAVDPDEDGHVSWDEYK--NDTYGSVGDDEEnvadni 112

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 4506025   91 -----------KLRFAFRIYDMDKDGYISNGELFQVLKMMVGNNLKDTQLQQIVDktiiNADKDGDGRISFEEF 153
Cdd:cd15899 113 kedeeykklllKDKKRFEAADQDGDLILTLEEFLAFLHPEESPYMLDFVIKETLE----DLDKNGDGFISLEEF 182

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4506025   27 FKKLDLDNSGSLSVEEFMSLPEL--QQNPLVQRVIDI------------------FDTDGNGEVDFKEFIEGVSQFsvkg 86
Cdd:cd15900   6 FKMFDLDGDGELDKEEFNKVQSIirSQTSVGQRHRDHtngestklgmnstlaryfFGKDGKQKLSIEKFLEFQENL---- 81

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 4506025   87 dkeQK----LRFAFRIYDMdKDGYISNGELFQVLKMMVGNNLKDtqlqQIVDKTIINADKDGDGRISFEEFCAV 156
Cdd:cd15900  82 ---QEeiddVDTALTFYHL-AGASIDRKTFKRAAKVVAGVELSD----HVVDVVFTIFDEDGDGILSHKEFISV 147

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4506025   16 DADEIKRLGKRFKKLDLDNSGSLSVEEFMSLpelqqnplvqrvIDIFDTDGNGEVDFKEFIEGVSQFsvkgdkeQKLRFA 95
Cdd:cd16182  17 DAVELQKLLNASLLKDMPKFDGFSLETCRSL------------IALMDTNGSGRLDLEEFKTLWSDL-------KKWQAI 77

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 4506025   96 FRIYDMDKDGYISNGELFQVLK---MMVGNNLkdtqLQQIVDKTIinadkDGDGRISFEEF--CAV 156
Cdd:cd16182  78 FKKFDTDRSGTLSSYELRKALEsagFHLSNKV----LQALVLRYA-----DSTGRITFEDFvsCLV 134

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+.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4506025   27 FKKLDLDnSGSLSVEEFMSL--------PELQQNPLVQR-VIDIFDTDGNGEVDFKEFiEGVSQFsVKGDKEqklrfAFR 97
Cdd:cd15897   6 FQAVAGD-DGEISATELQQAlsnvgwthFDLGFSLETCRsMIAMMDRDHSGKLNFSEF-KGLWNY-IKAWQE-----IFR 77

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 4506025   98 IYDMDKDGYISNGELFQVLKMMvGNNLKDTQLQQIVDKTiinadKDGDGRISFEEF 153
Cdd:cd15897  78 TYDTDGSGTIDSNELRQALSGA-GYRLSEQTYDIIIRRY-----DRGRGNIDFDDF 127

phosphatidylserine decarboxylase

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4506025    36 GSLSVEEFMSLPELQQNPLVQRVIDIFDTDGNGEVDFKEFIEGVSQF--SVKGDKEQKLrfaFRIYDMDKDGYISNGELF 113
Cdd:PLN02964 162 GSIFVSCSIEDPVETERSFARRILAIVDYDEDGQLSFSEFSDLIKAFgnLVAANKKEEL---FKAADLNGDGVVTIDELA 238

                 ...
gi 4506025   114 QVL 116
Cdd:PLN02964 239 ALL 241

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.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 4506025  104 DGYISNGELFQVLKMMVGNNLKDTQLQQIVDKTIINADKDGDGRISFEEFCAVVGGL--DIHKKM 166
Cdd:cd00213  24 KDTLSKKELKELLETELPNFLKNQKDPEAVDKIMKDLDVNKDGKVDFQEFLVLIGKLavACHEFF 88

Cytoskeletal-regulatory complex EF hand; This is an efhand family from the N-terminal of actin cytoskeleton-regulatory complex END3 and similar proteins from fungi and closely related species.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 4506025    103 KDGYISNGELFQVLKmmvGNNLKDTQLQQIVDKtiinADKDGDGRISFEEFC 154
Cdd:pfam12763  22 ENNKLTGDQVSPVLK---NSRLPDDQLAKIWDL----ADIDSDGKLDFEEFC 66

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).

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 4506025   92 LRFAFRIYDMDKDGYISNGELFQVLKMmvGNNLKDtqlQQIVDKTIINADKDGDGRISFEEF 153
Cdd:cd16185   2 LRQWFRAVDRDRSGSIDVNELQKALAG--GGLLFS---LATAEKLIRMFDRDGNGTIDFEEF 58