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
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1907132918 206 ELRIAFREFDKDRDGRITVAELRQAAPAlLGEPLEGTELDEMLREMDLNGDGTIDFD 262
Cdd:cd00051     1 ELREAFRLFDKDGDGTISADELKAALKS-LGEGLSEEEIDEMIREVDKDGDGKIDFE 56

EF-hand domain pair;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1907132918 206 ELRIAFREFDKDRDGRITVAELRQA-APALLGEPLEGTELDEMLREMDLNGDGTIDFD 262
Cdd:pfam13499   3 KLKEAFKLLDSDGDGYLDVEELKKLlRKLEEGEPLSDEEVEELFKEFDLDKDGRISFE 60

centrin; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907132918 133 AFEEFDTDQDGYIGYRELGDCMRTLGYMPTEMELLEVSQHVKMRMGGFVDFEEFVELISPKL-----REETAHMlgvrel 207
Cdd:PTZ00183   22 AFDLFDTDGSGTIDPKELKVAMRSLGFEPKKEEIKQMIADVDKDGSGKIDFEEFLDIMTKKLgerdpREEILKA------ 95

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1907132918 208 riaFREFDKDRDGRITVAELRQAApALLGEPLEGTELDEMLREMDLNGDGTIDFD 262
Cdd:PTZ00183   96 ---FRLFDDDKTGKISLKNLKRVA-KELGETITDEELQEMIDEADRNGDGEISEE 146

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907132918 131 QAAFEEFDTDQDGYIgyrELGDCMRTLGYMPTEMELLEVSQHvkmrmGGFVDFEEFVELIsPKLREETAHmlgvRELRIA 210
Cdd:COG5126     8 DRRFDLLDADGDGVL---ERDDFEALFRRLWATLFSEADTDG-----DGRISREEFVAGM-ESLFEATVE----PFARAA 74

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1907132918 211 FREFDKDRDGRITVAELRQAAPALlgePLEGTELDEMLREMDLNGDGTIDFD 262
Cdd:COG5126    75 FDLLDTDGDGKISADEFRRLLTAL---GVSEEEADELFARLDTDGDGKISFE 123

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 1907132918 131 QAAFEEFDTDQDGYIGYRELGDCMRTLGY-MPTEMELLEVSQHVKMRMGGfVDFEEFVELispklreetahMLGVRELRI 209
Cdd:cd16180    70 RRLFRRFDRDRSGSIDFNELQNALSSFGYrLSPQFVQLLVRKFDRRRRGS-ISFDDFVEA-----------CVTLKRLTD 137

                          90
                  ....*....|....
gi 1907132918 210 AFREFDKDRDGRIT 223
Cdd:cd16180   138 AFRKYDTNRTGYAT 151

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 1907132918 134 FEEFDTDQDGYIGYRELgdCMRTLGYMPTEME----------LLEVSQHVKMRMG------GFVDFEEFVELISPklrEE 197
Cdd:cd16227    78 FEEADEDGDGKVTWEEY--LADSFGYDDEDNEemikdsteddLKLLEDDKEMFEAadlnkdGKLDKTEFSAFQHP---EE 152

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1907132918 198 TAHMLGVrELRIAFREFDKDRDGRITVAEL------RQAAPALLgeplegTELDEMLREMDLNGDGTID 260
Cdd:cd16227   153 YPHMHPV-LIEQTLRDKDKDNDGFISFQEFlgdragHEDKEWLL------VEKDRFDEDYDKDGDGKLD 214

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 1907132918 134 FEEFDTDQDGYIGYRELGDCMRTLGYMPTEME---LLevsqhvkMRM-----GGFVDFEEFVELISPklreetahmlgVR 205
Cdd:cd16180     6 FQAVDRDRSGRISAKELQRALSNGDWTPFSIEtvrLM-------INMfdrdrSGTINFDEFVGLWKY-----------IQ 67

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1907132918 206 ELRIAFREFDKDRDGRITVAELRQaapAL--LGEPLEGTELDEMLREMDLNGDGTIDFD 262
Cdd:cd16180    68 DWRRLFRRFDRDRSGSIDFNELQN---ALssFGYRLSPQFVQLLVRKFDRRRRGSISFD 123

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
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1907132918 206 ELRIAFREFDKDRDGRITVAELRQA-APALLGEPLEGTEldEMLREMDLNGDGTIDF 261
Cdd:cd16185     1 ELRQWFRAVDRDRSGSIDVNELQKAlAGGGLLFSLATAE--KLIRMFDRDGNGTIDF 55

EF-hand domain pair;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907132918 131 QAAFEEFDTDQDGYIGYRELGDCMRTLGymptemellevsqhvkmrmggfvdfeefvelISPKLREEtahmlgvrELRIA 210
Cdd:pfam13499   5 KEAFKLLDSDGDGYLDVEELKKLLRKLE-------------------------------EGEPLSDE--------EVEEL 45

                          90       100
                  ....*....|....*....|.
gi 1907132918 211 FREFDKDRDGRITVAELRQAA 231
Cdd:pfam13499  46 FKEFDLDKDGRISFEEFLELY 66

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 1907132918 206 ELRIAFREFDKDRDGRITVAELRQA 230
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKEL 25

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 1907132918 179 GFVDFEEFV-ELISPKLREETAHMLGVRELRiaFREF-DKDRDGRITVAELRQ-AAPALLGEPLEgtELDEMLREMDLNG 255
Cdd:cd15899   175 GFISLEEFIsDPYSADENEEEPEWVKVEKER--FVELrDKDKDGKLDGEELLSwVDPSNQEIALE--EAKHLIAESDENK 250

                  ....*..
gi 1907132918 256 DGTIDFD 262
Cdd:cd15899   251 DGKLSPE 257

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 1907132918 134 FEEFDTDQDGYIGYRELGDCMRTLGYMPTEMELLEVSQHVKMRMGGFVDFEEFVELIspklreetaHMLGVR-ELRIAFR 212
Cdd:cd15898     6 WIKADKDGDGKLSLKEIKKLLKRLNIRVSEKELKKLFKEVDTNGDGTLTFDEFEELY---------KSLTERpELEPIFK 76

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1907132918 213 EFDKDRDGRITVAELRQAAPALLGEPLEGTELDEMLREMDLNG-DGTIDFDG 263
Cdd:cd15898    77 KYAGTNRDYMTLEEFIRFLREEQGENVSEEECEELIEKYEPEReNRQLSFEG 128

EF-hand domain;

                          10        20
                  ....*....|....*....|....*...
gi 1907132918 131 QAAFEEFDTDQDGYIGYRELGDCMRTLG 158
Cdd:pfam13405   3 REAFKLFDKDGDGKISLEELRKALRSLG 30

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 1907132918 131 QAAFEEFDTDQDGYIGYRELGDCMRTLGYMPTEMELLEVSQHVKMRMGGFVDFEEFVELispklreeTAHMLGVRELria 210
Cdd:cd16185    69 QNGFEQRDTSRSGRLDANEVHEALAASGFQLDPPAFQALFRKFDPDRGGSLGFDDYIEL--------CIFLASARNL--- 137

                          90
                  ....*....|....
gi 1907132918 211 FREFDKDRDGRITV 224
Cdd:cd16185   138 FQAFDRQRTGRVTL 151

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 1907132918 206 ELRIAFREFDKDRDGRITVAELRQAAPALLGEPLEGTELDEMLREMDLNGDGTIDFDG 263
Cdd:cd16180     1 ELRRIFQAVDRDRSGRISAKELQRALSNGDWTPFSIETVRLMINMFDRDRSGTINFDE 58

EF hand;

                          10        20
                  ....*....|....*....|...
gi 1907132918 207 LRIAFREFDKDRDGRITVAELRQ 229
Cdd:pfam13202   1 LKDTFRQIDLNGDGKISKEELRR 23

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 1907132918 131 QAAFEEFDTDQDGYIGYRELGDCMRTLGY---MPTEMELLEVSQHVKM-----RM--------GGFVDFEEFVELISPkl 194
Cdd:cd15899    74 KEQFRAVDPDEDGHVSWDEYKNDTYGSVGddeENVADNIKEDEEYKKLllkdkKRfeaadqdgDLILTLEEFLAFLHP-- 151

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907132918 195 rEETAHMLGVReLRIAFREFDKDRDGRITVAE----LRQAAPALLGEPLEGTELDEMLREMDLNGDGTID 260
Cdd:cd15899   152 -EESPYMLDFV-IKETLEDLDKNGDGFISLEEfisdPYSADENEEEPEWVKVEKERFVELRDKDKDGKLD 219

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 1907132918 131 QAAFEEFDTDQDGYIGYRELGDcMRTLGYMPTEMELleVSQHVKM---RMGGFVDFEEFVELispklreetaH--MLGVR 205
Cdd:cd16185     3 RQWFRAVDRDRSGSIDVNELQK-ALAGGGLLFSLAT--AEKLIRMfdrDGNGTIDFEEFAAL----------HqfLSNMQ 69

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1907132918 206 ElriAFREFDKDRDGRITVAELRQAApALLGEPLEGTELDEMLREMDLNGDGTIDFDG 263
Cdd:cd16185    70 N---GFEQRDTSRSGRLDANEVHEAL-AASGFQLDPPAFQALFRKFDPDRGGSLGFDD 123

EF-hand, calcium binding motif, found in reticulocalbin-2 (RCN2); RCN2, also termed calcium-binding protein ERC-55, or E6-binding protein (E6BP), or TCBP-49, is an endoplasmic reticulum resident low-affinity Ca2+-binding protein that has been implicated in immunity, redox homeostasis, cell cycle regulation and coagulation. It is associated with tumorigenesis, in particular with transformation of cells of the cervix induced by human papillomavirus (HPV), through binding to human papillomavirus (HPV) E6 oncogenic protein. It specifically interacts with vitamin D receptor among nuclear receptors. RCN2 contains an N-terminal signal sequence followed by six copies of the EF-hand Ca2+-binding motif, and 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 1907132918 179 GFVDFEEFV-ELISPKLREETAHMLGVRELRIAfREFDKDRDGRITVAE-LRQAAPALLGepLEGTELDEMLREMDLNGD 256
Cdd:cd16224   176 GFISLEEFLgDYRKDPTANEDPEWIIVEKDRFV-NDYDKDNDGKLDPQElLPWVVPNNYG--IAQEEALHLIDEMDLNGD 252

                  .
gi 1907132918 257 G 257
Cdd:cd16224   253 G 253

EF-hand domain pair;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1907132918 178 GGFVDFEEFVELISPKLReetaHMLGVRELRIAFREFDKDRDGRITVAELRQAA 231
Cdd:pfam13833   2 KGVITREELKRALALLGL----KDLSEDEVDILFREFDTDGDGYISFDEFCVLL 51

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 1907132918 133 AFEEFDTDQDGYIGYRELGDCMRTLgymptemeLLEVSQHVKmrmggfvdfeefveliSPKLREETAHMLgvrelriafR 212
Cdd:cd15902    95 IWRKYDTDGSGFIEAKELKGFLKDL--------LLKNKKHVS----------------PPKLDEYTKLIL---------K 141

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1907132918 213 EFDKDRDGRITVAELRQAAP----------ALLGEPLEGTELDEMLREMDLNGDGTID 260
Cdd:cd15902   142 EFDANKDGKLELDEMAKLLPvqenfllkfqILGAMDLTKEDFEKVFEHYDKDNNGVIE 199

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.

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                  ....*....|....*....|....*....|....*....|....*....|..
gi 1907132918 211 FREFDKDRDGRITVAELRQAAPAlLGEPLEGTELDEMLREMDLNGDGTIDFD 262
Cdd:cd16183    73 FRSFDRDNSGNIDKNELKQALTS-FGYRLSDQFYDILVRKFDRQGRGTIAFD 123

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907132918 134 FEEFDTDQDGYIGYRELGDCMRTLGY--MPTEMELLeVSQHVKmrmGGFVDFEEFVELiSPKLREETAHmlgvrelriaF 211
Cdd:cd16181    76 FMQYDRDRSGTVEPQELQQAIRSFGYnlSPQALNVI-VKRYSK---NGRITFDDFVAC-AVRLRALTDR----------F 140

                          90
                  ....*....|..
gi 1907132918 212 REFDKDRDGRIT 223
Cdd:cd16181   141 RRRDTQQNGTAT 152

calmodulin; Provisional

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                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1907132918 133 AFEEFDTDQDGYIGYRELGDCMRTLGYMPTEMELLEVSQHVKMRMGGFVDFEEFVELISPK 193
Cdd:PTZ00184   89 AFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMMMSK 149

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907132918 211 FREFDKDRDGRITVAElrqAAPALLGEPLEGTELDEMLREMDLNGDGTIDFDGESPYRHL 270
Cdd:cd00052     5 FRSLDPDGDGLISGDE---ARPFLGKSGLPRSVLAQIWDLADTDKDGKLDKEEFAIAMHL 61

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.

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                  ....*....|....*....|....*....|....*....|....*....|..
gi 1907132918 179 GFVDFEEFVELispklreetahMLGVRELRIAFREFDKDRDGRITVAELRQA 230
Cdd:cd16182    57 GRLDLEEFKTL-----------WSDLKKWQAIFKKFDTDRSGTLSSYELRKA 97