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 1937369935  65 YAQHVFRSFDANSDGTLDFKEYVIALHMTTAGKPTQKLEWAFSLYDVDGNGTISKNEVLEIVM 127
Cdd:cd00051     1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

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 1937369935  101 KLEWAFSLYDVDGNGTISKNEVLEIVMAI 129
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

calmodulin; Provisional

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1937369935  67 QHVFRSFDANSDGTLDFKEYVIAlhMTTAGKPT---QKLEWAFSLYDVDGNGTISKNEVLEIVMAIFKMIKPEDVKNL 141
Cdd:PTZ00184   50 QDMINEVDADGNGTIDFPEFLTL--MARKMKDTdseEEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEM 125

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 1937369935  65 YAQHVFRSFDANSDGTLDFKEYVIALHMTTAGKPTQKLEWAFSLYDVDGNGTISKNEVLEIVM 127
Cdd:cd00051     1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

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        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1937369935  27 ELSAWYQSFLKECpSGRITRQEFESIYSK---FFPDSDpkayAQHVFRSFDANSDGTLDFKEYViALHmttagKPTQKLE 103
Cdd:cd16185     1 ELRQWFRAVDRDR-SGSIDVNELQKALAGgglLFSLAT----AEKLIRMFDRDGNGTIDFEEFA-ALH-----QFLSNMQ 69

                          90       100
                  ....*....|....*....|.
gi 1937369935 104 WAFSLYDVDGNGTISKNEVLE 124
Cdd:cd16185    70 NGFEQRDTSRSGRLDANEVHE 90

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 1937369935   5 KSGALSKEileELQL------NTKFTEEELSAWYQSFLKEcPSGRITRQEFESIYsKFFpdsdpkAYAQHVFRSFDANSD 78
Cdd:cd16180    13 RSGRISAK---ELQRalsngdWTPFSIETVRLMINMFDRD-RSGTINFDEFVGLW-KYI------QDWRRLFRRFDRDRS 81

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1937369935  79 GTLDFKEYVIALHMTTAGKPTQKLEWAFSLYDVDGNGTIS 118
Cdd:cd16180    82 GSIDFNELQNALSSFGYRLSPQFVQLLVRKFDRRRRGSIS 121

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1937369935  63 KAYAQHVFRSFDANSDGTLDFKEYVIALHMTTAGKPT--QKLEWAFSLYDVDGNGTISKNEVLEIVM 127
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRKLEEGEPLsdEEVEELFKEFDLDKDGRISFEEFLELYS 67

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 1937369935  41 SGRITRQEFESIYSKFF-----PDSDPKA--YAQHVFRSFDANSDGTLDFKEYVIAL------HMTTAGKPTQKL----- 102
Cdd:cd15902   104 SGFIEAKELKGFLKDLLlknkkHVSPPKLdeYTKLILKEFDANKDGKLELDEMAKLLpvqenfLLKFQILGAMDLtkedf 183

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1937369935 103 EWAFSLYDVDGNGTISKNEVLEIVMAIFKMIKPEdvknlpDDENTPEKRAEKIWAFFGKKDDDKLTEEE 171
Cdd:cd15902   184 EKVFEHYDKDNNGVIEGNELDALLKDLLEKNKAD------IDKPDLENFRDAILRACDKNKDGKIQKTE 246

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 1937369935  49 FESIYSKFFPDSDP---KAYAQHVFRSFDANSDGTLDFKEYVIALHMTTAGKPTQKLEWAFSLYDVDGNGTISKNEVLEI 125
Cdd:cd15899    17 LGKEEAEEFDQLTPeesKRRLGVIVSKMDVDKDGFISAKELHSWILESFKRHAMEESKEQFRAVDPDEDGHVSWDEYKND 96

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|
gi 1937369935 126 VMAIFKMIKPEDVKNLPDDENTPE--KRAEKIWAFFGKKDDDKLTEEEFI 173
Cdd:cd15899    97 TYGSVGDDEENVADNIKEDEEYKKllLKDKKRFEAADQDGDLILTLEEFL 146

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.

                          10        20
                  ....*....|....*....|....*....
gi 1937369935 101 KLEWAFSLYDVDGNGTISKNEVLEIVMAI 129
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLKKL 29

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1937369935 106 FSLYDVDGNGTISKNEVLEIVMAIfkmikpedvkNLPDDEntpekrAEKIWAFFGKKDDDKLTEEEFI 173
Cdd:cd00052     5 FRSLDPDGDGLISGDEARPFLGKS----------GLPRSV------LAQIWDLADTDKDGKLDKEEFA 56

calmodulin; Provisional

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1937369935  67 QHVFRSFDANSDGTLDFKEYVIAlhMTTAGKPT---QKLEWAFSLYDVDGNGTISKNEVLEIVMAIFKMIKPEDVKNL 141
Cdd:PTZ00184   50 QDMINEVDADGNGTIDFPEFLTL--MARKMKDTdseEEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEM 125

EF-hand domain pair;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1937369935  40 PSGRITRQEFESIYSKF----FPDSDpkayAQHVFRSFDANSDGTLDFKEYVIAL 90
Cdd:pfam13833   1 EKGVITREELKRALALLglkdLSEDE----VDILFREFDTDGDGYISFDEFCVLL 51