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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386869273  75 SGVVNEETFKQIYAQFFphgdastyaHYLFNAFDTTQTGSVKFEDFVTALSILLRGTVHEKLRWTFNLYDINKDGYINKE 154
Cdd:COG5126   19 DGVLERDDFEALFRRLW---------ATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISAD 89

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 386869273 155 EMMDIVKAIydmmgkytypvlkeDTPRQHVDVFFQKMDKNKDGIVTLDEFLESCQE 210
Cdd:COG5126   90 EFRRLLTAL--------------GVSEEEADELFARLDTDGDGKISFEEFVAAVRD 131

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386869273  75 SGVVNEETFKQIYAQFFphgdastyaHYLFNAFDTTQTGSVKFEDFVTALSILLRGTVHEKLRWTFNLYDINKDGYINKE 154
Cdd:COG5126   19 DGVLERDDFEALFRRLW---------ATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISAD 89

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 386869273 155 EMMDIVKAIydmmgkytypvlkeDTPRQHVDVFFQKMDKNKDGIVTLDEFLESCQE 210
Cdd:COG5126   90 EFRRLLTAL--------------GVSEEEADELFARLDTDGDGKISFEEFVAAVRD 131

EF-hand domain pair;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 386869273  134 EKLRWTFNLYDINKDGYINKEEMMDIVKAIYdmmgkytypvLKEDTPRQHVDVFFQKMDKNKDGIVTLDEFLE 206
Cdd:pfam13499   2 EKLKEAFKLLDSDGDGYLDVEELKKLLRKLE----------EGEPLSDEEVEELFKEFDLDKDGRISFEEFLE 64

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386869273  75 SGVVNEETFKQIYAQFFphgdastyaHYLFNAFDTTQTGSVKFEDFVTALSILLRGTVHEKLRWTFNLYDINKDGYINKE 154
Cdd:COG5126   19 DGVLERDDFEALFRRLW---------ATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISAD 89

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 386869273 155 EMMDIVKAIydmmgkytypvlkeDTPRQHVDVFFQKMDKNKDGIVTLDEFLESCQE 210
Cdd:COG5126   90 EFRRLLTAL--------------GVSEEEADELFARLDTDGDGKISFEEFVAAVRD 131

EF-hand domain pair;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 386869273  134 EKLRWTFNLYDINKDGYINKEEMMDIVKAIYdmmgkytypvLKEDTPRQHVDVFFQKMDKNKDGIVTLDEFLE 206
Cdd:pfam13499   2 EKLKEAFKLLDSDGDGYLDVEELKKLLRKLE----------EGEPLSDEEVEELFKEFDLDKDGRISFEEFLE 64

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.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 386869273 134 EKLRWTFNLYDINKDGYINKEEMMDIVkaiYDMMgkytypvlkedtPRQH-VDVFFQKMDKNKDGIVTLDEFLE 206
Cdd:cd00252   45 EIAQWEFDNLDNNKDGKLDKRELAPFR---APLM------------PLEHcARGFFESCDLNKDKKISLQEWLG 103

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.

                           10        20
                   ....*....|....*....|....*....
gi 386869273   135 KLRWTFNLYDINKDGYINKEEMMDIVKAI 163
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

EF-hand-like motif found in the dystrophin/dystrobrevin/dystrotelin family; The dystrophin/dystrobrevin/dystrotelin family has been characterized by a compact cluster of domains comprising four EF-hand-like motifs and a ZZ-domain, followed by a looser region with two coiled-coils. Dystrophin is the founder member of this family. It is a sub-membrane cytoskeletal protein associated with the inner surface membrane. Dystrophin and its close paralog utrophin have a large N-terminal extension of actin-binding CH domains, up to 24 spectrin repeats, and a WW domain. Its further paralog, dystrophin-related protein 2 (DRP-2), retains only two of the spectrin repeats. Dystrophin, utrophin or DRP2 can form the core of a membrane-bound complex consisting of dystroglycan, sarcoglycans and syntrophins, known as the dystrophin-glycoprotein complex (DGC) that plays an important role in brain development and disease, as well as in the prevention of muscle damage. Dystrobrevins, including alpha- and beta-dystrobrevin, lack the large N-terminal extension found in dystrophin, but alpha-dystrobrevin has a characteristic C-terminal extension. Dystrobrevins are part of the DGC. They physically associate with members of the dystrophin family and with the syntrophins through their homologous C-terminal coiled coil motifs. In contrast, dystrotelins lack both the large N-terminal extension found in dystrophin and the obvious syntrophin-binding sites (SBSs). Dystrotelins are not critical for mammalian development. They may be involved in other forms of cytokinesis. Moreover, dystrotelin is unable to heterodimerize with members of the dystrophin or dystrobrevin families, or to homodimerize.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 386869273 103 LFNAFDTTQTGSVKFEDFVTALSILLRGTVHEKLRWTFNLYDiNKDGYINKE-------EMMDIVKAIY 164
Cdd:cd15901   59 LLNLYDRNRTGCIRLLSVKIALITLCAASLLDKYRYLFGQLA-DSSGFISRErltqflqDLLQIPDLIG 126

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 386869273 140 FNLYDINKDGYINKEEMMdivkaiydmmgKYTYPvlkEDTPRQH---VDVFFQKMDKNKDGIVTLDEFL 205
Cdd:cd16227  128 FEAADLNKDGKLDKTEFS-----------AFQHP---EEYPHMHpvlIEQTLRDKDKDNDGFISFQEFL 182

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

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 386869273   103 LFNAFDTTQTGSVKFEDfvtALSIL----LRGTVHEKLrWtfNLYDINKDGYINKEEMMDIVKAIYDMMGKYTYP 173
Cdd:smart00027  15 IFRSLDKNQDGTVTGAQ---AKPILlksgLPQTLLAKI-W--NLADIDNDGELDKDEFALAMHLIYRKLNGYPIP 83

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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386869273  99 YAHYLFNAFDTTQTGSVKFEDFVTALSILlrgTVHEKLRWTFNLYDINKDGYINKEEMMDIVKAiydmmgkytypVLKED 178
Cdd:cd15898   37 ELKKLFKEVDTNGDGTLTFDEFEELYKSL---TERPELEPIFKKYAGTNRDYMTLEEFIRFLRE-----------EQGEN 102

                         90       100
                 ....*....|....*....|....*...
gi 386869273 179 TPRQHVDVFFQKMDKN-KDGIVTLDEFL 205
Cdd:cd15898  103 VSEEECEELIEKYEPErENRQLSFEGFT 130

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 386869273 103 LFNAFDTTQTGSVKFEDFVTALSILLRgtvhekLRWTFNLYDINKDGY--INKEEMMDIV 160
Cdd:cd16180  108 LVRKFDRRRRGSISFDDFVEACVTLKR------LTDAFRKYDTNRTGYatISYEDFLTMV 161

Secreted protein acidic and rich in cysteine Ca binding region; The SPARC_Ca_bdg domain of Secreted Protein Acidic and Rich in Cysteine is responsible for the anti-spreading activity of human urothelial cells. It is rich in alpha-helices. This extracellular calcium-binding domain contains two EF-hands that each coordinates one Ca2+ ion, forming a helix-loop-helix structure that not only drives the conformation of the protein but is also necessary for biological activity. The anti-spreading activity was dependent on the coordination of Ca2+ by a Glu residue at the Z position of EF-hand 2.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 386869273  138 WTFNLYDINKDGYINKEEMmDIVKAIYDMMGKYTYPvlkedtprqhvdvFFQKMDKNKDGIVTLDEFLE 206
Cdd:pfam10591  57 WMFKRLDTNDDLLLDHEEL-APIRAPLKPEEHCIKP-------------FFESCDANKDKLISLEEWCC 111