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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 75337581  71 ILQAFKLIDRDNDGAVSRHDLESLLSRLgpdplteeeINVMLKEVDCDGDGTIRLEELASRVVSLDPARDSTELKETFEF 150
Cdd:COG5126   7 LDRRFDLLDADGDGVLERDDFEALFRRL---------WATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDL 77

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
gi 75337581 151 FDADRDGLISADELLRVFSTIGDERCTLDDckrMIADVDEDGDGFVCFTEFSRMM 205
Cdd:COG5126  78 LDTDGDGKISADEFRRLLTALGVSEEEADE---LFARLDTDGDGKISFEEFVAAV 129

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 75337581    70 EILQAFKLIDRDNDGAVSRHDLESLLSRLGPD-PLTEEEINVMLKEVDCDGDGTIRLEELA 129
Cdd:pfam13499   3 KLKEAFKLLDSDGDGYLDVEELKKLLRKLEEGePLSDEEVEELFKEFDLDKDGRISFEEFL 63

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 75337581  111 MLKEVDCDGDGTIRLEELASRVVSLDPARDSTELKETFEFFDADRDGLISADEL---LRVFSTIGDERCTLDDCKRMIAD 187
Cdd:NF041410  32 LFAKLDSDGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDELaaaAPPPPPPPDQAPSTELADDLLSA 111

                         90
                 ....*....|....*
gi 75337581  188 VDEDGDGFVCFTEFS 202
Cdd:NF041410 112 LDTDGDGSISSDELS 126

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 75337581   75 FKLIDRDNDGAVSRHDLESLLSRLGPDPLTEEeinvMLKEVDCDGDGTIRLEELAS 130
Cdd:NF041410 109 LSALDTDGDGSISSDELSAGLTSAGSSADSSQ----LFSALDSDGDGSVSSDELAA 160

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 75337581  71 ILQAFKLIDRDNDGAVSRHDLESLLSRLgpdplteeeINVMLKEVDCDGDGTIRLEELASRVVSLDPARDSTELKETFEF 150
Cdd:COG5126   7 LDRRFDLLDADGDGVLERDDFEALFRRL---------WATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDL 77

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
gi 75337581 151 FDADRDGLISADELLRVFSTIGDERCTLDDckrMIADVDEDGDGFVCFTEFSRMM 205
Cdd:COG5126  78 LDTDGDGKISADEFRRLLTALGVSEEEADE---LFARLDTDGDGKISFEEFVAAV 129

centrin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 75337581   70 EILQAFKLIDRDNDGAVSRHDLESLLSRLGPDPlTEEEINVMLKEVDCDGDGTIRLEELASRVVSLDPARDSTE-LKETF 148
Cdd:PTZ00183  18 EIREAFDLFDTDGSGTIDPKELKVAMRSLGFEP-KKEEIKQMIADVDKDGSGKIDFEEFLDIMTKKLGERDPREeILKAF 96

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 75337581  149 EFFDADRDGLISADELLRVFSTIGdERCTLDDCKRMIADVDEDGDGFVCFTEFSRMM 205
Cdd:PTZ00183  97 RLFDDDKTGKISLKNLKRVAKELG-ETITDEELQEMIDEADRNGDGEISEEEFYRIM 152

calmodulin; Provisional

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 75337581   70 EILQAFKLIDRDNDGAVSRHDLESLLSRLGpDPLTEEEINVMLKEVDCDGDGTIRLEELASRVVS 134
Cdd:PTZ00184  85 EIKEAFKVFDRDGNGFISAAELRHVMTNLG-EKLTDEEVDEMIREADVDGDGQINYEEFVKMMMS 148

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 75337581  63 PSPYSYVEILQAFKLIDRDNDGAVSR-------HDLESLLSRLGPDPLTEEEINVMLKEVDCDGDGTIRLEELAS----- 130
Cdd:cd15902  84 QPLISSVEFMKIWRKYDTDGSGFIEAkelkgflKDLLLKNKKHVSPPKLDEYTKLILKEFDANKDGKLELDEMAKllpvq 163

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 75337581 131 ----RVVSLDPARDST--ELKETFEFFDADRDGLISADELLRVFSTIG------DERCTLDDCKRMI-ADVDEDGDGFVC 197
Cdd:cd15902 164 enflLKFQILGAMDLTkeDFEKVFEHYDKDNNGVIEGNELDALLKDLLeknkadIDKPDLENFRDAIlRACDKNKDGKIQ 243

                ...
gi 75337581 198 FTE 200
Cdd:cd15902 244 KTE 246

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

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 75337581  70 EILQAFKLIDRDNDGAVSRHDLESLLSRLGpdpLTEEEINVMLKEVDCDGDGTIRLEELASRV 132
Cdd:COG5126  70 FARAAFDLLDTDGDGKISADEFRRLLTALG---VSEEEADELFARLDTDGDGKISFEEFVAAV 129

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 75337581  75 FKLIDRDNDGAVSRHDLESLLSRLGPDPLTEEEINVMLKEVDCDGDGTIRLEELAS--RVVsldpardsTELKETFEFFD 152
Cdd:cd16183   6 FQRVDKDRSGQISATELQQALSNGTWTPFNPETVRLMIGMFDRDNSGTINFQEFAAlwKYI--------TDWQNCFRSFD 77

                        90       100
                ....*....|....*....|
gi 75337581 153 ADRDGLISADELLRVFSTIG 172
Cdd:cd16183  78 RDNSGNIDKNELKQALTSFG 97

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 75337581 107 EINVMLKEVDCDGDGTIRLEELASRVVSLDPARDSTELKETFEFFDADRDGLISADELLRVFS 169
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

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 75337581  71 ILQAFKLIDRDNDGAVSRHDLESLLSRLGPdPLTEEEINVMLKEVDCDGDGTIRLEELasrVVSLDPARDSTELKETFEF 150
Cdd:cd15898   2 LRRQWIKADKDGDGKLSLKEIKKLLKRLNI-RVSEKELKKLFKEVDTNGDGTLTFDEF---EELYKSLTERPELEPIFKK 77

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 75337581 151 FDADRDGLISADELLRVFSTIGDERCTLDDCKRMIADVDEDG-DGFVCFTEFSRMM 205
Cdd:cd15898  78 YAGTNRDYMTLEEFIRFLREEQGENVSEEECEELIEKYEPEReNRQLSFEGFTNFL 133

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 75337581  111 MLKEVDCDGDGTIRLEELASRVVSLDPARDSTELKETFEFFDADRDGLISADEL---LRVFSTIGDERCTLDDCKRMIAD 187
Cdd:NF041410  32 LFAKLDSDGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDELaaaAPPPPPPPDQAPSTELADDLLSA 111

                         90
                 ....*....|....*
gi 75337581  188 VDEDGDGFVCFTEFS 202
Cdd:NF041410 112 LDTDGDGSISSDELS 126

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 75337581  75 FKLIDRDNDGAVSRHDLESLLSRlGPDPLTEEEINVMLKEVDCDGDGTIRLEELASRVVSLDP--------ARDSTEL-- 144
Cdd:cd16227  42 AKKMDLNDDGFIDRKELKAWILR-SFKMLDEEEANERFEEADEDGDGKVTWEEYLADSFGYDDedneemikDSTEDDLkl 120

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 75337581 145 ----KETFEFFDADRDGLISADELLRVFSTIGDERCTLDDCKRMIADVDEDGDGFVCFTEF 201
Cdd:cd16227 121 leddKEMFEAADLNKDGKLDKTEFSAFQHPEEYPHMHPVLIEQTLRDKDKDNDGFISFQEF 181

EF-hand, calcium binding motif, found in beta-parvalbumin; Beta-parvalbumin, also termed Oncomodulin-1 (OM), is a small calcium-binding protein that is expressed in hepatomas, as well as in the blastocyst and the cytotrophoblasts of the placenta. It is also found to be expressed in the cochlear outer hair cells of the organ of Corti and frequently expressed in neoplasms. Mammalian beta-parvalbumin is secreted by activated macrophages and neutrophils. It may function as a tissue-specific Ca2+-dependent regulatory protein, and may also serve as a specialized cytosolic Ca2+ buffer. Beta-parvalbumin acts as a potent growth-promoting signal between the innate immune system and neurons in vivo. It has high and specific affinity for its receptor on retinal ganglion cells (RGC) and functions as the principal mediator of optic nerve regeneration. It exerts its effects in a cyclic adenosine monophosphate (cAMP)-dependent manner and can further elevate intracellular cAMP levels. Moreover, beta-parvalbumin is associated with efferent function and outer hair cell electromotility, and can identify different hair cell types in the mammalian inner ear. Beta-parvalbumin is characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. The EF site displays a high-affinity for Ca2+/Mg2+, and the CD site is a low-affinity Ca2+-specific site. In addition, beta-parvalbumin is distinguished from other parvalbumins by its unusually low isoelectric point (pI = 3.1) and sequence eccentricities (e.g., Y57-L58-D59 instead of F57-I58-E59).

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 75337581 138 ARDSTELKETFEFFDADRDGLISADEL---LRVFSTIGDErCTLDDCKRMIADVDEDGDGFVCFTEFSRM 204
Cdd:cd16255  30 KKSADDVKKVFEIIDQDKSGFIEEEELklfLQNFSSGARE-LTDAETKAFLKAGDSDGDGKIGVEEFQAL 98

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 75337581   105 EEEINVMLKEVDCDGDGTIRLEELAS--RVVSLDPARDSTELKETFEFFDADRDGLISADELLRVFS 169
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKllRKLEEGEPLSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 75337581  72 LQAFKLIDRDNDGAVSRHDLESLLSRL-------GPDPLT---EEEINVMLKEVDCDGDGTIRLEELAsRVVSLDP---- 137
Cdd:cd16177   2 LEIWKHFDADGNGYIEGKELENFFRELerarrgaGVDSKSanfGEKMKEFMQKYDKNADGRIEMAELA-QILPTEEnfll 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 75337581 138 -----ARDSTELKETFEFFDADRDGLISADELLRVFSTI-------GDERCTLDDCKRMIADVDEDGDGFVCFTEFSRMM 205
Cdd:cd16177  81 cfrqhVGSSSEFMEAWRKYDTDRSGYIEANELKGFLSDLlkkanrpYDEKKLQEYTQTILRMFDLNGDGKLGLSEMARLL 160

                ...
gi 75337581 206 DLQ 208
Cdd:cd16177 161 PVQ 163

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
                ....*....|....*....|....*....|....*....|....*....|...
gi 75337581 153 ADRDGLISADELLRVFSTIG----DERCTLDDCKRMIADVDEDGDGFVCFTEF 201
Cdd:cd15897  10 AGDDGEISATELQQALSNVGwthfDLGFSLETCRSMIAMMDRDHSGKLNFSEF 62

EF-hand, calcium binding motif, found in secretagogin (SCGN); 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 calcium sensor/coincidence detector modulating vesicular exocytosis of neurotransmitters, neuropeptides or hormones. It also serves as a calcium buffer in neurons. Thus, SCGN may be linked to the pathogenesis of neurological diseases such as Alzheimer's, and also acts as a serum marker of neuronal damage, or as a tumor biomarker. SCGN consists of the three globular domains each of which contains a pair of EF-hand motifs. All six EF hand motifs of SCGN in some eukaryotes, including D. rerio, X. laevis, M. domestica, G. gallus, O. anatinus, could potentially bind six calcium ions. In contrast, SCGNs from higher eukaryotes have at least one non-functional EF-hand motif due to the mutation(s) or deletions. For instance, the EF1 loop does not coordinate calcium ion due to the key residue asparagine replaced by lysine in SCGNs of many mammalian species. Moreover, the EF2 loop seems to be competent for calcium-binding in most mammalian SCGNs except for human and chimpanzee orthologs.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 75337581  68 YVEILQAFkliDRDNDGAVSRHDLES----LLSRLGP-DPLTEEEINVM----LKEVDCDGDGTIRLEELASRVVSLD-- 136
Cdd:cd16178   1 FAEIWQHF---DADESGYIEGKELDNffkdLLKKLGTkDTISADEVQDVkecfMSAYDVTGDGRIQIQELANIILPDDen 77

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 75337581 137 ---------PARDSTELKETFEFFDADRDGLISADELLRVFSTIGDERCTLDDCKR-------MIADVDEDGDGFVCFTE 200
Cdd:cd16178  78 fllffrreePLDSSVEFMRIWRKYDADSSGYISAAELKNFLRDLFLQHKKVITEDKldeytdtMMKIFDKNKDGRLDLND 157

                ....*...
gi 75337581 201 FSRMMDLQ 208
Cdd:cd16178 158 MARILALQ 165

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 75337581  83 DGAVSRHDLESLLSRLG----PDPLTEEEINVMLKEVDCDGDGTIRLEELASRVVSLDpardstELKETFEFFDADRDGL 158
Cdd:cd16181  13 DGQIDADELQRCLTQSGisgnYQPFSLETCRLMIAMLDRDHSGKMGFNEFKELWAALN------QWKTTFMQYDRDRSGT 86

                        90
                ....*....|....
gi 75337581 159 ISADELLRVFSTIG 172
Cdd:cd16181  87 VEPQELQQAIRSFG 100

EF-hand domain;

                          10        20        30
                  ....*....|....*....|....*....|
gi 75337581    70 EILQAFKLIDRDNDGAVSRHDLESLLSRLG 99
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSLG 30

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 75337581  75 FKLIDRDNDGAVSRHDLESLLSRLGPDPLTEEEINVMLKEVDCDGDGTIRLEELASRVVSLDPARDSTELKETFE-FFDA 153
Cdd:cd16227 128 FEAADLNKDGKLDKTEFSAFQHPEEYPHMHPVLIEQTLRDKDKDNDGFISFQEFLGDRAGHEDKEWLLVEKDRFDeDYDK 207

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 75337581 154 DRDGLISADELLRvFSTIGDERCTLDDCKRMIADVDEDGDGFVCFTE 200
Cdd:cd16227 208 DGDGKLDGEEILS-WLVPDNEEIAEEEVDHLFASADDDHDDRLSFDE 253

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 75337581  75 FKLIDRDNDGAVSRHDLESLLSRlGPDPLTEEEINVMLKEVDCDGDGTIRLEELASRV----------VSLDPARDSTE- 143
Cdd:cd15899  41 VSKMDVDKDGFISAKELHSWILE-SFKRHAMEESKEQFRAVDPDEDGHVSWDEYKNDTygsvgddeenVADNIKEDEEYk 119

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 75337581 144 -----LKETFEFFDADRDGLISADELLrVFSTIGDERCTLD-DCKRMIADVDEDGDGFVCFTEF 201
Cdd:cd15899 120 klllkDKKRFEAADQDGDLILTLEEFL-AFLHPEESPYMLDfVIKETLEDLDKNGDGFISLEEF 182

EF-hand, calcium binding motif, found in calbindin (CB); CB, also termed calbindin D28, or D-28K, or avian-type vitamin D-dependent calcium-binding protein, is a unique intracellular calcium binding protein that functions as both a calcium sensor and buffer in eukaryotic cells, which undergoes a conformational change upon calcium binding and protects cells against insults of high intracellular calcium concentration. CB is highly expressed in brain and sensory neurons. It plays essential roles in neural functioning, altering synaptic interactions in the hippocampus, modulating calcium channel activity, calcium transients, and intrinsic neuronal firing activity. It prevents a neuronal death, as well as maintains and controls calcium homeostasis. CB also modulates the activity of proteins participating in the development of neurodegenerative disorders such as Alzheimer's disease, Huntington's disease, and bipolar disorder. Moreover, CB interacts with Ran-binding protein M, a protein known to involve in microtubule function. It also interacts with alkaline phosphatase and myo-inositol monophosphatase, as well as caspase 3, an enzyme that plays an important role in the regulation of apoptosis. CB contains six EF-hand motifs in a single globular domain, where EF-hands 1, 3, 4, 5 bind four calcium ions with high affinity.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 75337581  67 SYVEILQAFKLIDRDNDGAVSRHDLESLLSRL-------GPDPLTEEEINVMLKEVDCDGDGTIRLEELASrvvsLDPAR 139
Cdd:cd16176  83 SSEEFMQTWRKYDADHSGFIEADELKSFLKDLlkkankpFDESKLEEYTHTMLKMFDSNNDGKLGLTEMAR----LLPVQ 158

                        90       100       110
                ....*....|....*....|....*....|....*..
gi 75337581 140 D------------STELKETFEFFDADRDGLISADEL 164
Cdd:cd16176 159 EnfllkfqgvkmcGKEFNKIFELYDQDGNGYIDENEL 195

EF-hand, calcium binding motif, found in parvalbumins; Parvalbumins are small, acidic, cytosolic EF-hand-containing Ca2+-buffer and Ca2+ transporter/shuttle proteins belonging to EF-hand superfamily. They are expressed by vertebrates in fast-twitch muscle cells, specific neurons of the central and peripheral nervous system, sensory cells of the mammalian auditory organ (Corti's cell), and some other cells, and characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. Thus, they may play an additional role in Mg2+ handling. Moreover, parvalbumins represent one of the major animal allergens. In metal-bound states, parvalbumins possess a rigid and stable tertiary structure and display strong allergenicity. In contrast, the metal-free parvalbumins are intrinsically disordered, and the loss of metal ions results in a conformational change that decreases their IgE binding capacity. Furthermore, parvalbumins have been widely used as a neuronal marker for a variety of functional brain systems. They also function as a Ca2+ shuttle transporting Ca2+ from troponin-C (TnC) to the sarcoplasmic reticulum (SR) Ca2+ pump during muscle relaxation. Thus they may facilitate myocardial relaxation and play important roles in cardiac diastolic dysfunction. Parvalbumins consists of alpha- and beta- sublineages, which can be distinguished on the basis of isoelectric point (pI > 5 for alpha; pI

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 75337581  70 EILQAFKLIDRDNDGAVSRHDLESLLSRLGPDP--LTEEEINVMLKEVDCDGDGTIRLEELASRV 132
Cdd:cd16253  35 DIKKVFNILDQDKSGFIEEEELKLFLKNFSDGArvLSDKETKNFLAAGDSDGDGKIGVDEFKSMV 99

EF-hand, calcium binding motif, found in parvalbumins; Parvalbumins are small, acidic, cytosolic EF-hand-containing Ca2+-buffer and Ca2+ transporter/shuttle proteins belonging to EF-hand superfamily. They are expressed by vertebrates in fast-twitch muscle cells, specific neurons of the central and peripheral nervous system, sensory cells of the mammalian auditory organ (Corti's cell), and some other cells, and characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. Thus, they may play an additional role in Mg2+ handling. Moreover, parvalbumins represent one of the major animal allergens. In metal-bound states, parvalbumins possess a rigid and stable tertiary structure and display strong allergenicity. In contrast, the metal-free parvalbumins are intrinsically disordered, and the loss of metal ions results in a conformational change that decreases their IgE binding capacity. Furthermore, parvalbumins have been widely used as a neuronal marker for a variety of functional brain systems. They also function as a Ca2+ shuttle transporting Ca2+ from troponin-C (TnC) to the sarcoplasmic reticulum (SR) Ca2+ pump during muscle relaxation. Thus they may facilitate myocardial relaxation and play important roles in cardiac diastolic dysfunction. Parvalbumins consists of alpha- and beta- sublineages, which can be distinguished on the basis of isoelectric point (pI > 5 for alpha; pI

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 75337581 138 ARDSTELKETFEFFDADRDGLISADEL---LRVFSTiGDERCTLDDCKRMIADVDEDGDGFVCFTEFSRM 204
Cdd:cd16253  30 KKSPADIKKVFNILDQDKSGFIEEEELklfLKNFSD-GARVLSDKETKNFLAAGDSDGDGKIGVDEFKSM 98

EF hand;

                          10        20
                  ....*....|....*....|....
gi 75337581   144 LKETFEFFDADRDGLISADELLRV 167
Cdd:pfam13202   1 LKDTFRQIDLNGDGKISKEELRRL 24

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        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 75337581  60 PEVPSPYSYVEILQAFKLIDRDNDGAVSRHDLESLLSRLGPDPLTE--EEINVMLKEVDCDGDGTIRLEE-----LASRV 132
Cdd:cd16225  25 EEDSEPKKRKKLKEIFKKVDVNTDGFLSAEELEDWIMEKTQEHFQEavEENEQIFKAVDTDKDGNVSWEEyrvhfLLSKG 104

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 75337581 133 VSLDPARDSTELKET---------------FEFFDAD--RDGLISADELLRVF----STIGDERCTLDdckrMIADVDED 191
Cdd:cd16225 105 YSEEEAEEKIKNNEElkldeddkevldrykDRWSQADepEDGLLDVEEFLSFRhpehSRGMLKNMVKE----ILHDLDQD 180

                       170
                ....*....|...
gi 75337581 192 GDGFVCFTEFSRM 204
Cdd:cd16225 181 GDEKLTLDEFVSL 193

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 75337581  87 SRHDLESLLSR--------LGPDPlTEEEINVMLKEVDCDGDGTIRLEELASRVVSLDPARDSTELKETFEFFDADRDGL 158
Cdd:cd15899   9 SDYDHEAFLGKeeaeefdqLTPEE-SKRRLGVIVSKMDVDKDGFISAKELHSWILESFKRHAMEESKEQFRAVDPDEDGH 87

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 75337581 159 ISADELLRVF--STIGDE-------------RCTLDDCKRMIADVDEDGDGFVCFTEF 201
Cdd:cd15899  88 VSWDEYKNDTygSVGDDEenvadnikedeeyKKLLLKDKKRFEAADQDGDLILTLEEF 145

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 75337581  71 ILQAFKLIDRDNDGAVSrhdLESLLSRLGPDPLTEEEINVMLKE-------VDCDGDGTIRLEELASRVVSLDPARDSTE 143
Cdd:cd15899 162 IKETLEDLDKNGDGFIS---LEEFISDPYSADENEEEPEWVKVEkerfvelRDKDKDGKLDGEELLSWVDPSNQEIALEE 238

                        90       100
                ....*....|....*....|..
gi 75337581 144 LKETFEFFDADRDGLISADELL 165
Cdd:cd15899 239 AKHLIAESDENKDGKLSPEEIL 260

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 75337581    182 KRMIADVDEDGDGFVCFTEFSRMM 205
Cdd:smart00054   3 KEAFRLFDKDGDGKIDFEEFKDLL 26