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        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 153945858  93 KLKWTFKIYDKDGNGCIDRLELLNIVEGIYqlkkacrrelqteqgqLLTPEEVVDRIFLLVDENGDGQLSLNEFVEGAR 171
Cdd:cd00051    1 ELREAFRLFDKDGDGTISADELKAALKSLG----------------EGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

EF-hand domain pair;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 153945858   93 KLKWTFKIYDKDGNGCIDRLELLNIVEGIyqlkkacrrelqtEQGQLLTPEEVvDRIFLLVDENGDGQLSLNEFVEGAR 171
Cdd:pfam13499   3 KLKEAFKLLDSDGDGYLDVEELKKLLRKL-------------EEGEPLSDEEV-EELFKEFDLDKDGRISFEEFLELYS 67

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        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 153945858  93 KLKWTFKIYDKDGNGCIDRLELLNIVEGIYqlkkacrrelqteqgqLLTPEEVVDRIFLLVDENGDGQLSLNEFVEGAR 171
Cdd:cd00051    1 ELREAFRLFDKDGDGTISADELKAALKSLG----------------EGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153945858  61 MFRAFDKNGDNTIDFLEYVAALNLVLRGT-LEHKLKWTFKIYDKDGNGCIDRLELlnivegiyqlkkacrRELQTEQGQL 139
Cdd:PTZ00184  52 MINEVDADGNGTIDFPEFLTLMARKMKDTdSEEEIKEAFKVFDRDGNGFISAAEL---------------RHVMTNLGEK 116

                         90       100
                 ....*....|....*....|....*...
gi 153945858 140 LTPEEvVDRIFLLVDENGDGQLSLNEFV 167
Cdd:PTZ00184 117 LTDEE-VDEMIREADVDGDGQINYEEFV 143

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153945858  34 SGTLFMHEFKRFFKVTDDEEASQYVEGMFRAFDKNGDNTIDFLEYVAALNlVLRGTLEHkLKWTFKIYDKDGNGCIDRLE 113
Cdd:COG5126   47 DGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISADEFRRLLT-ALGVSEEE-ADELFARLDTDGDGKISFEE 124

                         90
                 ....*....|
gi 153945858 114 LLNIVEGIYQ 123
Cdd:COG5126  125 FVAAVRDYYT 134

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 153945858  34 SGTLFMHEFKRFFK--------VTDDEEASQYVEGMFRAFDKNGDNTIDFLEYVAAL----NLVLRGTLEHKLKWT---- 97
Cdd:cd15902  104 SGFIEAKELKGFLKdlllknkkHVSPPKLDEYTKLILKEFDANKDGKLELDEMAKLLpvqeNFLLKFQILGAMDLTkedf 183

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 153945858  98 ---FKIYDKDGNGCIDRLELLNIVEGIYQLKKAcRRELQTEqgqlltpEEVVDRIFLLVDENGDGQLSLNEFV 167
Cdd:cd15902  184 ekvFEHYDKDNNGVIEGNELDALLKDLLEKNKA-DIDKPDL-------ENFRDAILRACDKNKDGKIQKTELA 248

centrin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153945858  34 SGTLFMHEFKRFFKVTDDEEASQYVEGMFRAFDKNGDNTIDFLEY--VAALNLVLRGTLEHKLKwTFKIYDKDGNGCIDr 111
Cdd:PTZ00183  31 SGTIDPKELKVAMRSLGFEPKKEEIKQMIADVDKDGSGKIDFEEFldIMTKKLGERDPREEILK-AFRLFDDDKTGKIS- 108

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 153945858 112 lellnivegIYQLKKACRrelqtEQGQLLTPEEVVDRIFLlVDENGDGQLSLNEFVEGARRD 173
Cdd:PTZ00183 109 ---------LKNLKRVAK-----ELGETITDEELQEMIDE-ADRNGDGEISEEEFYRIMKKT 155

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.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153945858  98 FKIYDKDGNGCIDRLELLNIVegiyqlkkacrrelqteqGQLLTPEEVVDRIFLLVDENGDGQLSLNEFV 167
Cdd:cd00052    5 FRSLDPDGDGLISGDEARPFL------------------GKSGLPRSVLAQIWDLADTDKDGKLDKEEFA 56

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 153945858  58 VEGMFRAFDKNGDNTIDFLEYVAALNLVLRgtlehklkWT--FKIYDKDGNGCIDRLELLNIVEGI-YQLkkacrrelqt 134
Cdd:cd16180   39 VRLMINMFDRDRSGTINFDEFVGLWKYIQD--------WRrlFRRFDRDRSGSIDFNELQNALSSFgYRL---------- 100

                         90       100       110
                 ....*....|....*....|....*....|....
gi 153945858 135 eqgqlltPEEVVDRIFLLVDENGDGQLSLNEFVE 168
Cdd:cd16180  101 -------SPQFVQLLVRKFDRRRRGSISFDDFVE 127

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 153945858  14 GEIDVAELQEWykkfvmecpsgtlFMHEFKRFfkvtddeeASQYVEGMFRAFDKNGDNTIDFLEY-VAALNLVLRGTLEH 92
Cdd:cd15899   50 GFISAKELHSW-------------ILESFKRH--------AMEESKEQFRAVDPDEDGHVSWDEYkNDTYGSVGDDEENV 108

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153945858  93 ---------------KLKWTFKIYDKDGNGCIDRLELLNivegiyqlkkacrrelqteqgqLLTPEE-------VVDRIF 150
Cdd:cd15899  109 adnikedeeykklllKDKKRFEAADQDGDLILTLEEFLA----------------------FLHPEEspymldfVIKETL 166

                        170
                 ....*....|....*..
gi 153945858 151 LLVDENGDGQLSLNEFV 167
Cdd:cd15899  167 EDLDKNGDGFISLEEFI 183

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 153945858  40 HEFKRFFKVTddeeasqyVEGMFRAFDKNGDNTIDFLEYVAalnlvlrGTLEHKLKWTFKI--------YDKDGNGCIDR 111
Cdd:cd16227  151 EEYPHMHPVL--------IEQTLRDKDKDNDGFISFQEFLG-------DRAGHEDKEWLLVekdrfdedYDKDGDGKLDG 215

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 153945858 112 LELLNIVegIYQLKKacrrelqteqgqllTPEEVVDRIFLLVDENGDGQLSLNEFVE 168
Cdd:cd16227  216 EEILSWL--VPDNEE--------------IAEEEVDHLFASADDDHDDRLSFDEILD 256

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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153945858  38 FMHEFKRFFKVTDD---EEASQYVEGMFRAFDKNGDNTIDFLEYVAAL----NLVLRGTLEHKLKWT-------FKIYDK 103
Cdd:cd16179  120 FLKHLLKEAKRDNDvseDKLIEYTDTILQLFDRNKDGKLQLSEMARLLpvkeNFLCRPIFKGAGKLTredidrvFALYDR 199

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 153945858 104 DGNGCIDRLELLNIVEGIYQLKKacrrELQTEQGQLLTPEEVVDRifllVDENGDGQLSLNE 165
Cdd:cd16179  200 DNNGTIENEELTGFLKDLLELVQ----EDYDEQDLEEFKEIILRG----WDFNNDGKISRKE 253

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
                 ....*....|....*....|....*....|....*....|...
gi 153945858  37 LFMHEFKRFFKVTDDEEasqYVEGMFRAFDKNGDNTIDFLEYV 79
Cdd:cd00213   35 LLETELPNFLKNQKDPE---AVDKIMKDLDVNKDGKVDFQEFL 74

EF-hand, calcium binding motif, found in calretinin (CR); CR, also termed 29 kDa calbindin, 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 possibly functions as a calcium buffer, calcium sensor, and apoptosis regulator, which may be implicated in many biological processes, including cell proliferation, differentiation, and cell death. CR contains six EF-hand motifs within two independent domains, CR I-II and CR III-VI. CR I-II consists of EF-hand motifs 1 and 2, and CR III-VI consists of EF-hand motifs 3-6. The first 5 EF-hand motifs are capable of binding calcium ions, while the EF-hand 6 is inactive. Thus, CR has two pairs of cooperative binding sites (I-II and III-IV), which display high affinity calcium-binding sites, and one independent calcium ion-binding site (V), which displays lower affinity binding.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153945858  50 DDEEASQYVEGMFRAFDKNGDNTIDFLEYVAAL----NLVLR----GTLEHKLKWTFKIYDKDGNGCIDRLELLNIVEGI 121
Cdd:cd16177  128 DEKKLQEYTQTILRMFDLNGDGKLGLSEMARLLpvqeNFLLKfqgmKLSSEEFNAIFAFYDKDGSGYIDENELDALLKDL 207

                 ..
gi 153945858 122 YQ 123
Cdd:cd16177  208 YE 209

centrin; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 153945858  91 EHKLKWTFKIYDKDGNGCIDRLELlnivegiyqlkKACRRELQTEqgqllTPEEVVDRIFLLVDENGDGQLSLNEFVE 168
Cdd:PTZ00183  16 KKEIREAFDLFDTDGSGTIDPKEL-----------KVAMRSLGFE-----PKKEEIKQMIADVDKDGSGKIDFEEFLD 77