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 6677693   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 6677693     101 KLEWAFSLYDVDGNGTISKNEVLEIVMAI 129
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

calmodulin; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 6677693    67 QHVFRSFDANSDGTLDFKEYVIAlhMTTAGKPT---QKLEWAFSLYDVDGNGTISKNEVLEIVMAIFKMIKPEDV 138
Cdd:PTZ00184  50 QDMINEVDADGNGTIDFPEFLTL--MARKMKDTdseEEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEV 122

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 6677693   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 6677693   27 ELSAWYQSFLKECpSGRITRQEFESIYSK---FFPDSDpkayAQHVFRSFDANSDGTLDFKEYViALHmttagKPTQKLE 103
Cdd:cd16185   1 ELRQWFRAVDRDR-SGSIDVNELQKALAGgglLFSLAT----AEKLIRMFDRDGNGTIDFEEFA-ALH-----QFLSNMQ 69

                        90       100
                ....*....|....*....|.
gi 6677693  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 6677693    5 KSGALSKEileELQL------NTKFTEEELSAWYQSFLKEcPSGRITRQEFESIYsKFFpdsdpkAYAQHVFRSFDANSD 78
Cdd:cd16180  13 RSGRISAK---ELQRalsngdWTPFSIETVRLMINMFDRD-RSGTINFDEFVGLW-KYI------QDWRRLFRRFDRDRS 81

                        90       100       110       120
                ....*....|....*....|....*....|....*....|
gi 6677693   79 GTLDFKEYVIALHMTTAGKPTQKLEWAFSLYDVDGNGTIS 118
Cdd:cd16180  82 GSIDFNELQNALSSFGYRLSPQFVQLLVRKFDRRRRGSIS 121

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 6677693     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 6677693   41 SGRITRQEFESIYSKFF-----PDSDPKA--YAQHVFRSFDANSDGTLDFKEYVIAL------HMTTAGKPTQKL----- 102
Cdd:cd15902 104 SGFIEAKELKGFLKDLLlknkkHVSPPKLdeYTKLILKEFDANKDGKLELDEMAKLLpvqenfLLKFQILGAMDLtkedf 183

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 6677693  103 EWAFSLYDVDGNGTISKNEVLEIVMAIFKMIKPEdvkllpDDENTPEKRAEKIWAFFGKKEDDKLTEEE 171
Cdd:cd15902 184 EKVFEHYDKDNNGVIEGNELDALLKDLLEKNKAD------IDKPDLENFRDAILRACDKNKDGKIQKTE 246

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 6677693   42 GRITRQEFesiySKFF-PDSDPKAYA---QHVFRSFDANSDGTLDFKEYV--IALHMTTAGKPTQKLEWAFsLYDVDGNG 115
Cdd:cd16227 137 GKLDKTEF----SAFQhPEEYPHMHPvliEQTLRDKDKDNDGFISFQEFLgdRAGHEDKEWLLVEKDRFDE-DYDKDGDG 211

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 6677693  116 TISKNEVLEIVmaifkmikpedvklLPDDENTPEKRAEKIWAFFGKKEDDKLTEEEFIE 174
Cdd:cd16227 212 KLDGEEILSWL--------------VPDNEEIAEEEVDHLFASADDDHDDRLSFDEILD 256

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
                ....*....|....*....|....*....|....*....|....*....|.
gi 6677693   73 FDANSDGTLDFKEYViALHMTTAgkptqklEW--AFSLYDVDGNGTISKNE 121
Cdd:cd16180  46 FDRDRSGTINFDEFV-GLWKYIQ-------DWrrLFRRFDRDRSGSIDFNE 88

EF-hand domain;

                          10        20
                  ....*....|....*....|....*....
gi 6677693    101 KLEWAFSLYDVDGNGTISKNEVLEIVMAI 129
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSL 29

EF-hand domain pair;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 6677693     40 PSGRITRQEFESIYSKF----FPDSDpkayAQHVFRSFDANSDGTLDFKEYVIAL 90
Cdd:pfam13833   1 EKGVITREELKRALALLglkdLSEDE----VDILFREFDTDGDGYISFDEFCVLL 51