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 13929432 163 ELRDAFREFDTNGDGEISTSELREAMRKLlGHQVGHRDIEEIIRDVDLNGDGRVDFEEFVRMMS 226
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSL-GEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 13929432   162 KELRDAFREFDTNGDGEISTSELREAMRKLLGHQVGHRD-IEEIIRDVDLNGDGRVDFEEFVRMMS 226
Cdd:pfam13499   2 EKLKEAFKLLDSDGDGYLDVEELKKLLRKLEEGEPLSDEeVEELFKEFDLDKDGRISFEEFLELYS 67

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 13929432  162 KELrdaFREFDTNGDGEISTSELREAMR-----KLLGhqvghrDIEEIIRDVDLNGDGRVDFEEFVRMM 225
Cdd:NF041410  30 KQL---FAKLDSDGDGSVSQDELSSALSsksddGSLI------DLSELFSDLDSDGDGSLSSDELAAAA 89

centrin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13929432   78 SLRPEEIEELREAFREFDKDKDGYINCRDLGNCMRTMGYMPTEMELIELSQQINMNLGGHVDFDDFVELMGPKLlaetAD 157
Cdd:PTZ00183  10 GLTEDQKKEIREAFDLFDTDGSGTIDPKELKVAMRSLGFEPKKEEIKQMIADVDKDGSGKIDFEEFLDIMTKKL----GE 85

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13929432  158 MIGVKELRDAFREFDTNGDGEISTSELREAMRKlLGHQVGHRDIEEIIRDVDLNGDGRVDFEEFVRMMSR 227
Cdd:PTZ00183  86 RDPREEILKAFRLFDDDKTGKISLKNLKRVAKE-LGETITDEELQEMIDEADRNGDGEISEEEFYRIMKK 154

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13929432  82 EEIEELREAFREFDKDKDGYINCRDLGNCMRTMgymptemeLIELSQQINMNLGGHVDFDDFVELMGPKLLAETADmigv 161
Cdd:COG5126   2 LQRRKLDRRFDLLDADGDGVLERDDFEALFRRL--------WATLFSEADTDGDGRISREEFVAGMESLFEATVEP---- 69

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 13929432 162 kELRDAFREFDTNGDGEISTSELREAMRkllGHQVGHRDIEEIIRDVDLNGDGRVDFEEFVRMM 225
Cdd:COG5126  70 -FARAAFDLLDTDGDGKISADEFRRLLT---ALGVSEEEADELFARLDTDGDGKISFEEFVAAV 129

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 13929432  86 ELREAFREFDKDKDGYINCRDLGNCMRTMGYMPTEMELIELsqQINM---NLGGHVDFDDFVELMgpkllaetadmigvK 162
Cdd:cd16180   1 ELRRIFQAVDRDRSGRISAKELQRALSNGDWTPFSIETVRL--MINMfdrDRSGTINFDEFVGLW--------------K 64

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 13929432 163 ELRD---AFREFDTNGDGEISTSELREAMRKlLGHQVGHRDIEEIIRDVDLNGDGRVDFEEFVRMM 225
Cdd:cd16180  65 YIQDwrrLFRRFDRDRSGSIDFNELQNALSS-FGYRLSPQFVQLLVRKFDRRRRGSISFDDFVEAC 129

calmodulin; Provisional

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 13929432  161 VKELRDAFREFDTNGDGEISTSELREAMRKLlGHQVGHRDIEEIIRDVDLNGDGRVDFEEFVRMMSR 227
Cdd:PTZ00184  10 IAEFKEAFSLFDKDGDGTITTKELGTVMRSL-GQNPTEAELQDMINEVDADGNGTIDFPEFLTLMAR 75

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13929432 136 GHVDFDDFVELMGPkllaetadmigvkELRDAFREFDTNGDGEISTSELREAMRKLLGhQVGHRDIEEIIRDVDLNGDGR 215
Cdd:COG5126  20 GVLERDDFEALFRR-------------LWATLFSEADTDGDGRISREEFVAGMESLFE-ATVEPFARAAFDLLDTDGDGK 85

                        90
                ....*....|.
gi 13929432 216 VDFEEFVRMMS 226
Cdd:COG5126  86 ISADEFRRLLT 96

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 13929432  87 LREAFREFDKDKDGYINCRDLGNCMRTMGYMPTEMELIELSQQINMNLGGHVDFDDFVELMgpKLLAETadmigvKELRD 166
Cdd:cd15898   2 LRRQWIKADKDGDGKLSLKEIKKLLKRLNIRVSEKELKKLFKEVDTNGDGTLTFDEFEELY--KSLTER------PELEP 73

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 13929432 167 AFREFDTNGDGEISTSELREAMRKLLGHQVGHRDIEEIIRDVDLNGDGR-VDFEEFVRMMS 226
Cdd:cd15898  74 IFKKYAGTNRDYMTLEEFIRFLREEQGENVSEEECEELIEKYEPERENRqLSFEGFTNFLL 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 13929432  89 EAFREFDKDKDGYINCRDLGNCMRTM-----GYMPTEMELIELSQQI----NMNLGGHVDFDDFVELMGP-----KLLAE 154
Cdd:cd15902   3 EVWMHFDADGNGYIEGKELDSFLRELlkalnGKDKTDDEVAEKKKEFmekyDENEDGKIEIRELANILPTeenflLLFRR 82

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 13929432 155 TADMIGVKELRDAFREFDTNGDGEISTSELREAMRKLLGHQVGHRD-------IEEIIRDVDLNGDGRVDFEEFVRMM 225
Cdd:cd15902  83 EQPLISSVEFMKIWRKYDTDGSGFIEAKELKGFLKDLLLKNKKHVSppkldeyTKLILKEFDANKDGKLELDEMAKLL 160

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13929432  84 IEELREAFREFDKDKDGYINCRDLGNCMRTMGYmptemeliELSQQI--------NMNLGGHVDFDDFVELmgpkllaet 155
Cdd:cd16183  66 ITDWQNCFRSFDRDNSGNIDKNELKQALTSFGY--------RLSDQFydilvrkfDRQGRGTIAFDDFIQC--------- 128

                        90       100
                ....*....|....*....|....*..
gi 13929432 156 adMIGVKELRDAFREFDTNGDGEISTS 182
Cdd:cd16183 129 --CVVLQTLTDSFRRYDTDQDGWIQIS 153

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13929432  92 REFDK--DKDGYINCRDLGN----CMRTMGYMPTEMELIELSQQINM---NLGGHVDFDDFVELMgpkllaetadmIGVK 162
Cdd:cd16182   4 ELFEKlaGEDEEIDAVELQKllnaSLLKDMPKFDGFSLETCRSLIALmdtNGSGRLDLEEFKTLW-----------SDLK 72

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 13929432 163 ELRDAFREFDTNGDGEISTSELREAMRKlLGHQVGHRDIEEII-RDVDlnGDGRVDFEEFVRMMSR 227
Cdd:cd16182  73 KWQAIFKKFDTDRSGTLSSYELRKALES-AGFHLSNKVLQALVlRYAD--STGRITFEDFVSCLVR 135

The penta-EF hand (PEF) family; The penta-EF hand (PEF) family contains a group of five EF-hand calcium-binding proteins, including several classical calpain large catalytic subunits (CAPN1, 2, 3, 8, 9, 11, 12, 13, 14), two calpain small subunits (CAPNS1 and CAPNS2), as well as non-calpain PEF proteins, ALG-2 (apoptosis-linked gene 2, also termed programmed cell death protein 6, PDCD6), peflin, sorcin, and grancalcin. Based on the sequence similarity of EF1 hand, ALG-2 and peflin have been classified into group I PEF proteins. Calcium-dependent protease calpain subfamily members, sorcin and grancalcin, are group II PEF proteins. Calpains (EC 3.4.22.17) are calcium-activated intracellular cysteine proteases that play important roles in the degradation or functional modulation in a variety of substrates. They have been implicated in a number of physiological processes such as cell cycle progression, remodeling of cytoskeletal-cell membrane attachments, signal transduction, gene expression and apoptosis. ALG-2 is a pro-apoptotic factor that forms a homodimer in the cell or a heterodimer with its closest paralog peflin through their EF5s. Peflin is a 30-kD PEF protein with a longer N-terminal hydrophobic domain than any other member of the PEF family, and it contains nine nonapeptide (A/PPGGPYGGP) repeats. It exists only as a heterodimer with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+. ALG-2 interacts with various proteins in a Ca2+-dependent manner. Sorcin (for soluble resistance-related calcium binding protein) is a soluble resistance-related calcium-binding protein that participates in the regulation of calcium homeostasis in cells. Grancalcin is a cytosolic Ca2+-binding protein specifically expressed in neutrophils and monocytes/macrophages. It plays a key role in leukocyte-specific functions that are responsible for host defense. Grancalcin can form a heterodimer together with sorcin. Members in this family contain five EF-hand motifs attached to an N-terminal region of variable length containing one or more short Gly/Pro-rich sequences. These proteins form homodimers or heterodimers through pairing between the 5th EF-hands from the two molecules. Unlike calmodulin, the PEF domains do not undergo major conformational changes upon binding Ca2+.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13929432  84 IEELREAFREFDKDKDGYINCRDLGNCMRTMGYMPTEmeliELSQQINMNLG---GHVDFDDFVELmgpkllaetadMIG 160
Cdd:cd15897  69 IKAWQEIFRTYDTDGSGTIDSNELRQALSGAGYRLSE----QTYDIIIRRYDrgrGNIDFDDFIQC-----------CVR 133

                        90
                ....*....|....*....
gi 13929432 161 VKELRDAFREFDTNGDGEI 179
Cdd:cd15897 134 LQRLTDAFRRYDKDQDGQI 152

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 13929432  86 ELREAFREFDKDKDGYINCRDLGNcMRTMGYMPTEMELIElsQQINM---NLGGHVDFDDFVELMgpKLLAEtadmigvk 162
Cdd:cd16185   1 ELRQWFRAVDRDRSGSIDVNELQK-ALAGGGLLFSLATAE--KLIRMfdrDGNGTIDFEEFAALH--QFLSN-------- 67

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 13929432 163 eLRDAFREFDTNGDGEISTSELREAMRKlLGHQVGHRDIEEIIRDVDLNGDGRVDFEEFVRM 224
Cdd:cd16185  68 -MQNGFEQRDTSRSGRLDANEVHEALAA-SGFQLDPPAFQALFRKFDPDRGGSLGFDDYIEL 127

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

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 13929432 164 LRDAFREFDTNGDGEISTSELREAMrkllghqvgHRDIEEIIRDVDLNGDGRVDFEEFVRMMSR 227
Cdd:COG5126   7 LDRRFDLLDADGDGVLERDDFEALF---------RRLWATLFSEADTDGDGRISREEFVAGMES 61

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 13929432    163 ELRDAFREFDTNGDGEISTSELREAMRKL 191
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

EF-hand, calcium binding motif, found in peflin and similar proteins; Peflin, also termed penta-EF hand (PEF) protein with a long N-terminal hydrophobic domain, or penta-EF hand domain-containing protein 1, 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+. In lower vertebrates, peflin may interact with transient receptor potential N (TRPN1), suggesting a potential role of peflin in fast transducer channel adaptation.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13929432  84 IEELREAFREFDKDKDGYINCRDLGNCMRTMGYMPTEMELIELSQQINMNLGGHVDFDDFVELmgpkllaetadMIGVKE 163
Cdd:cd16184  66 IQQWKQVFQQFDRDRSGSIDENELHQALSQMGYRLSPQFVQFLVSKYDPRARRSLTLDQFIQV-----------CVQLQS 134

                        90
                ....*....|....*....
gi 13929432 164 LRDAFREFDTNGDGEISTS 182
Cdd:cd16184 135 LTDAFRQRDTQMTGTITIS 153

EF-hand domain;

                          10        20
                  ....*....|....*....|....*....
gi 13929432   163 ELRDAFREFDTNGDGEISTSELREAMRKL 191
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSL 29

EF-hand domain;

                          10        20        30
                  ....*....|....*....|....*....|
gi 13929432    86 ELREAFREFDKDKDGYINCRDLGNCMRTMG 115
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSLG 30

EF-hand motif found in phosphoinositide phospholipase C delta (PI-PLC-delta); PI-PLC-delta isozymes represent a class of metazoan PI-PLCs that are some of the most sensitive to calcium among all PLCs. Their activation is modulated by intracellular calcium ion concentration, phospholipids, polyamines, and other proteins, such as RhoAGAP. Like other PI-PLC isozymes, PI-PLC-delta isozymes contain 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 C-terminal C2 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. There are three PI-PLC-delta isozymes (1, 3 and 4). PI-PLC-delta1 is relatively well characterized. It is activated by high calcium levels generated by other PI-PLC family members, and therefore functions as a calcium amplifier within the cell. Different PI-PLC-delta isozymes have different tissue distribution and different subcellular locations. PI-PLC-delta1 is mostly a cytoplasmic protein, PI-PLC-delta3 is located in the membrane, and PI-PLC-delta4 is predominantly detected in the cell nucleus. PI-PLC-delta isozymes is evolutionarily conserved even in non-mammalian species, such as yeast, slime molds and plants.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 13929432 164 LRDAFREFDTNGDGEISTSELREAMRKlLGHQVGHRDIEEIIRDVDLNGDGRVDFEEFV----RMMSR 227
Cdd:cd16202   2 LKDQFRKADKNGDGKLSFKECKKLLKK-LNVKVDKDYAKKLFQEADTSGEDVLDEEEFVqfynRLTKR 68

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        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 13929432 175 GDGE-ISTSELREAMRK----LLGHQVGHRDIEEIIRDVDLNGDGRVDFEEFVRMM 225
Cdd:cd00213  22 GDKDtLSKKELKELLETelpnFLKNQKDPEAVDKIMKDLDVNKDGKVDFQEFLVLI 77

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 13929432    86 ELREAFREFDKDKDGYINCRDLGNCMRTM 114
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLKKL 29

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 13929432  85 EELREAFREFDKDKDGYINCRDLGNCMRTM----GYMPTEMELIELSQQI----NMNLGGHVDFDDFVELMGPKL-LAET 155
Cdd:cd15902  90 VEFMKIWRKYDTDGSGFIEAKELKGFLKDLllknKKHVSPPKLDEYTKLIlkefDANKDGKLELDEMAKLLPVQEnFLLK 169

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 13929432 156 ADMIGVKELR-----DAFREFDTNGDGEISTSELREAMRKLLGHQVGHRDIEE-------IIRDVDLNGDGRVDFEEFV 222
Cdd:cd15902 170 FQILGAMDLTkedfeKVFEHYDKDNNGVIEGNELDALLKDLLEKNKADIDKPDlenfrdaILRACDKNKDGKIQKTELA 248

EF-hand motif found in phosphoinositide phospholipase C eta (PI-PLC-eta); PI-PLC-eta isozymes represent a class of neuron-specific metazoan PI-PLCs that are most abundant in the brain, particularly in the hippocampus, habenula, olfactory bulb, cerebellum, and throughout the cerebral cortex. They are phosphatidylinositol 4,5-bisphosphate-hydrolyzing enzymes that are more sensitive to Ca2+ than other PI-PLC isozymes. They function as calcium sensors activated by small increases in intracellular calcium concentrations. They are also activated through G-protein-coupled receptor (GPCR) stimulation, and further mediate GPCR signalling pathways. PI-PLC-eta isozymes contain an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core domain, a C2 domain, and a unique C-terminal tail that terminates with a PDZ-binding motif, a potential interaction site for other signaling proteins. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. The C-terminal tail harbors a number of proline-rich motifs which may interact with SH3 (Src homology 3) domain-containing proteins, as well as many serine/threonine residues, suggesting possible regulation of interactions by protein kinases/phosphatases. There are two PI-PLC-eta isozymes (1-2). Aside from the PI-PLC-eta isozymes identified in mammals, their eukaryotic homologs are also present in this family.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 13929432 164 LRDAFREFDTNGDGEISTSELREAMRKLlghQVG--HRDIEEIIRDVDL-NGDGRVDFEEFV---RMMS 226
Cdd:cd16205   2 LKQTFEEADKNGDGLLSIGEILQLMHKL---NVNlpRRKVRQMFKEADTdDNQGTLDFEEFCafyKMMS 67

EF-hand, calcium binding motif, found in 45 kDa calcium-binding protein (Cab45); Cab45, also termed stromal cell-derived factor 4 (SDF-4), is a soluble, lumenal Golgi resident low-affinity Ca2+-binding protein that contains six copies of the EF-hand Ca2+-binding motif. It is required for secretory pathway calcium ATPase1 (SPCA1)-dependent Ca2+ import into the trans-Golgi network (TGN) and plays an essential role in Ca2+-dependent secretory cargo sorting at the TGN.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13929432 154 ETADMIGVKELRDAFREFDTNGDGEISTSELRE-AMRKLLGH-QVGHRDIEEIIRDVDLNGDGRVDFEEF 221
Cdd:cd16225  26 EDSEPKKRKKLKEIFKKVDVNTDGFLSAEELEDwIMEKTQEHfQEAVEENEQIFKAVDTDKDGNVSWEEY 95

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 13929432     86 ELREAFREFDKDKDGYINCRDLGNCMRTM 114
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

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 13929432  83 EIEELREAFRE-FDKDKDGYINCRDLGNcmrtmgYMPTEMELIELSQQINmnlgghvDFDDFVELMgpkllaetadmigv 161
Cdd:cd16179  46 ALEELKEEFMEaYDENQDGRIDIRELAQ------LLPTEENFLLLFRRDN-------PLDSSVEFM-------------- 98

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 13929432 162 kelrDAFREFDTNGDGEISTSELREAMRKLLGHQVGHRDIEE---------IIRDVDLNGDGRVDFEEFVRMM 225
Cdd:cd16179  99 ----KVWREYDKDNSGYIEADELKNFLKHLLKEAKRDNDVSEdklieytdtILQLFDRNKDGKLQLSEMARLL 167

N-terminal domain of Myosin essential light chain ELC; ELC is part of the apicomplexan membrane-associated protein complex called the glideosome, which is essential for parasite motility. The glideosome is composed of six proteins: myosin A (MyoA), essential light chain ELC, myosin light chain MLC1 (also called MTIP), and the glideosome-associated proteins GAP40, GAP45, and GAP50. MyoA is a Class XIV myosin implicated in gliding motility, as well as host cell and tissue invasion by parasites. ELC binds to the MyoA neck region adjacent to the MLC1-binding site, and both myosin light chains co-located to the glideosome. Although ELCs bind to a conserved MyoA sequence, P. falciparum ELC adopts a distinct structure in the free and MyoA-bound state. Therefore ELCs enhance MyoA performance by inducing alpha helical structure formation in MyoA and thus stiffening its lever arm. It has been shown that disruption of MyoA, MLC1, or ELC have dramatic effects on parasite motility but do not affect parasite shape or replication. The ELC N-terminal domain is part of the EF-hand calcium binding motif superfamily. Calcium binding has no effect on the structure of ELCs.

                        10        20
                ....*....|....*....|....*.
gi 13929432 164 LRDAFREFDTNGDGEISTSELREAMR 189
Cdd:cd22949   5 FREAFILFDRDGDGELTMYEAVLAMR 30

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13929432  91 FREFDKDKDGYINCRDLGNCMRTMGYMPTEMELIELsqQINM---NLGGHVDFDDFVELMgpKLlaetadmigVKELRDA 167
Cdd:cd16183   6 FQRVDKDRSGQISATELQQALSNGTWTPFNPETVRL--MIGMfdrDNSGTINFQEFAALW--KY---------ITDWQNC 72

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
gi 13929432 168 FREFDTNGDGEISTSELREAMRKlLGHQVGHRDIEEIIRDVDLNGDGRVDFEEFV 222
Cdd:cd16183  73 FRSFDRDNSGNIDKNELKQALTS-FGYRLSDQFYDILVRKFDRQGRGTIAFDDFI 126

S-100A1: S-100A1 domain found in proteins similar to S100A1. S100A1 is a calcium-binding protein belonging to a large S100 vertebrate-specific protein family within the EF-hand superfamily of calcium-binding proteins. Note that the S-100 hierarchy, to which this S-100A1 group belongs, contains only S-100 EF-hand domains, other EF-hands have been modeled separately. As is the case with many other members of S100 protein family, S100A1 is implicated in intracellular and extracellular regulatory activities, including interaction with myosin-associated twitchin kinase, actin-capping protein CapZ, sinapsin I, and tubulin. Structural data suggests that S100A1 proteins exist within cells as antiparallel homodimers, while heterodimers with S100A4 and S100B also has been reported. Upon binding calcium S100A1 changes conformation to expose a hydrophobic cleft which is the interaction site of S100A1 with its more that 20 known target proteins.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 13929432 178 EISTSELREAMRKLLGHQV-GHRD---IEEIIRDVDLNGDGRVDFEEFVRMMS 226
Cdd:cd05025  27 KLSKKELKDLLQTELSDFLdAQKDadaVDKIMKELDENGDGEVDFQEFVVLVA 79

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 13929432  162 KELrdaFREFDTNGDGEISTSELREAMR-----KLLGhqvghrDIEEIIRDVDLNGDGRVDFEEFVRMM 225
Cdd:NF041410  30 KQL---FAKLDSDGDGSVSQDELSSALSsksddGSLI------DLSELFSDLDSDGDGSLSSDELAAAA 89

S-100A10_like: S-100A10 domain found in proteins similar to S100A10. S100A10 is a member of the S100 family of EF-hand superfamily of calcium-binding proteins. Note that the S-100 hierarchy, to which this S-100A1_like group belongs, 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. A unique feature of S100A10 is that it contains mutation in both of the calcium binding sites, making it calcium insensitive. S100A10 has been detected in brain, heart, gastrointestinal tract, kidney, liver, lung, spleen, testes, epidermis, aorta, and thymus. Structural data supports the homo- and hetero-dimeric as well as hetero-tetrameric nature of the protein. S100A10 has multiple binding partners in its calcium free state and is therefore involved in many diverse biological functions.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 13929432 177 GEISTSELREAMRK----LLGHQVGHRDIEEIIRDVDLNGDGRVDFEEFV 222
Cdd:cd05031  25 NTLSRKELKKLMEKelseFLKNQKDPMAVDKIMKDLDQNRDGKVNFEEFV 74

S-100A13: S-100A13 domain found in proteins similar to S100A13. S100A13 is a calcium-binding protein belonging to a large S100 vertebrate-specific protein family within the EF-hand superfamily of calcium-binding proteins. Note that the S-100 hierarchy, to which this S-100A13 group belongs, contains only S-100 EF-hand domains, other EF-hands have been modeled separately. S100A13 is involved in the cellular export of interleukin-1 (IL-1) and of fibroblast growth factor-1 (FGF-1), which plays an important role in angiogenesis and tissue regeneration. Export is based on the CuII-dependent formation of multiprotein complexes containing the S100A13 protein. Assembly of these complexes occurs near the inner surface of the plasma membrane. Binding of two Ca(II) ions per monomer triggers key conformational changes leading to the creation of two identical and symmetrical Cu(II)-binding sites on the surface of the protein, close to the interface between the two monomers. These Cu(II)-binding sites are unique among the S100 proteins, which are reported to bind Cu(II) or Zn(II) ions in addition to Ca(II) ions. In addition, the three-dimensional structure of S100A13 differs significantly from those of other S100 proteins; the hydrophobic pocket that largely contributes to protein-protein interactions in other S100 proteins is absent in S100A13. The structure of S100A13 contains a large patch of negatively charged residues flanked by dense cationic clusters, formed mostly from positively charged residues from the C-terminal end, which plays major role in binding FGF-1.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 13929432 174 NGDGEISTSELREAMRKLLGHQV-GHRDIEEIIRDVDLNGDGRVDFEEFVRMM 225
Cdd:cd05022  21 GGKESLTASEFQELLTQQLPHLLkDVEGLEEKMKNLDVNQDSKLSFEEFWELI 73