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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 56699407  68 AEQFPKKIVQAGDKDLDGQLDFEEFVHY-----LQDHEKKLRLVFKSLDKKNDGRIDAQEIMQSLRDLGVkiSEQQAEKI 142
Cdd:COG5126  31 FRRLWATLFSEADTDGDGRISREEFVAGmeslfEATVEPFARAAFDLLDTDGDGKISADEFRRLLTALGV--SEEEADEL 108

                        90       100
                ....*....|....*....|....*
gi 56699407 143 LKSMDKNGTMTIDWNE----WRDYH 163
Cdd:COG5126 109 FARLDTDGDGKISFEEfvaaVRDYY 133

Mitochondrial carrier protein;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 56699407   296 ETLRIHERLVAGSLAGAIAQSSIYPMEVLKTRMAL---RKTGQYSGMLDCARRILAREGVAAFYKGYVPNMLGIIPYAGI 372
Cdd:pfam00153   1 SELSFLASLLAGGIAGAIAVTVTYPLDVVKTRLQVqggSGKSKGRGILDCFKKIYKEEGIRGLYKGLLPNLLRVAPAAAI 80

                          90
                  ....*....|....*.
gi 56699407   373 DLAVYETLKNAWLQHY 388
Cdd:pfam00153  81 YFGTYETLKRLLLKKL 96

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 56699407  73 KKIVQAGDKDLDGQLDFEEFVH---YLQDhekkLRLVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKSMDKN 149
Cdd:cd16185  39 EKLIRMFDRDGNGTIDFEEFAAlhqFLSN----MQNGFEQRDTSRSGRLDANEVHEALAASGFQLDPPAFQALFRKFDPD 114

                        90
                ....*....|
gi 56699407 150 GTMTIDWNEW 159
Cdd:cd16185 115 RGGSLGFDDY 124

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 56699407   39 DQMASF-----LGKQDGRAEATEKR-PTILLVVG--PAEQFPKKIVQAGDKDLDGQLDFEEFVHYLQ------DHEKKLR 104
Cdd:PTZ00184   8 EQIAEFkeafsLFDKDGDGTITTKElGTVMRSLGqnPTEAELQDMINEVDADGNGTIDFPEFLTLMArkmkdtDSEEEIK 87

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 56699407  105 LVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKSMDKNGTMTIDWNEW 159
Cdd:PTZ00184  88 EAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEF 142

Mitochondrial carrier protein;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 56699407   296 ETLRIHERLVAGSLAGAIAQSSIYPMEVLKTRMAL---RKTGQYSGMLDCARRILAREGVAAFYKGYVPNMLGIIPYAGI 372
Cdd:pfam00153   1 SELSFLASLLAGGIAGAIAVTVTYPLDVVKTRLQVqggSGKSKGRGILDCFKKIYKEEGIRGLYKGLLPNLLRVAPAAAI 80

                          90
                  ....*....|....*.
gi 56699407   373 DLAVYETLKNAWLQHY 388
Cdd:pfam00153  81 YFGTYETLKRLLLKKL 96

Mitochondrial carrier protein;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 56699407   394 DPGVFVLLACGTMSSTCGQLASYPLALVRTRMQAQASIEGAPEVTMSSLFKHILRTEGAFGLYRGLAPNFMKVIPAVSIS 473
Cdd:pfam00153   2 ELSFLASLLAGGIAGAIAVTVTYPLDVVKTRLQVQGGSGKSKGRGILDCFKKIYKEEGIRGLYKGLLPNLLRVAPAAAIY 81

                          90
                  ....*....|..
gi 56699407   474 YVVYENLKITLG 485
Cdd:pfam00153  82 FGTYETLKRLLL 93

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 56699407  73 KKIVQAGDKDLDGQLDFEEFVH---YLQDhekkLRLVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKSMDKN 149
Cdd:cd16185  39 EKLIRMFDRDGNGTIDFEEFAAlhqFLSN----MQNGFEQRDTSRSGRLDANEVHEALAASGFQLDPPAFQALFRKFDPD 114

                        90
                ....*....|
gi 56699407 150 GTMTIDWNEW 159
Cdd:cd16185 115 RGGSLGFDDY 124

ADP/ATP transporter on adenylate translocase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 56699407  210 LVAGGGAGAVSRTCTAPLD----RLKVLMQVHASRSNNmGIVGGFTQMIREGGARSLWRGNGINVLKIAPESAIKFMAYE 285
Cdd:PTZ00169 117 ILSGGLAGASSLLIVYPLDfartRLASDIGKGGDREFT-GLFDCLMKISKQTGFLSLYQGFGVSVQGIIVYRGAYFGLYD 195

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 56699407  286 QIKRLV-GSDQETLRIHERLVAGS---LAGAIAqssiYPMEVLKTRMAL---RKTG---QYSGMLDCARRILAREGVAAF 355
Cdd:PTZ00169 196 SAKALLfGNDKNTNILYKWAVAQTvtiLAGLIS----YPFDTVRRRMMMmsgRKAKseiQYTGTLDCWKKILKNEGLGGF 271

                 ....*....
gi 56699407  356 YKGYVPNML 364
Cdd:PTZ00169 272 FKGAWANVL 280

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 56699407   39 DQMASF-----LGKQDGRAEATEKR-PTILLVVG--PAEQFPKKIVQAGDKDLDGQLDFEEFVHYLQ------DHEKKLR 104
Cdd:PTZ00184   8 EQIAEFkeafsLFDKDGDGTITTKElGTVMRSLGqnPTEAELQDMINEVDADGNGTIDFPEFLTLMArkmkdtDSEEEIK 87

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 56699407  105 LVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKSMDKNGTMTIDWNEW 159
Cdd:PTZ00184  88 EAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEF 142

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 56699407  80 DKDLDGQLDFEEFV---HYLQDHEKklrlVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKSMDKNGTMTI 154
Cdd:cd16180  47 DRDRSGTINFDEFVglwKYIQDWRR----LFRRFDRDRSGSIDFNELQNALSSFGYRLSPQFVQLLVRKFDRRRRGSI 120

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 56699407  80 DKDLDGQLDFEEFV---HYLQDHEKklrlVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKSMDKNGTMTID 155
Cdd:cd16183  47 DRDNSGTINFQEFAalwKYITDWQN----CFRSFDRDNSGNIDKNELKQALTSFGYRLSDQFYDILVRKFDRQGRGTIA 121

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 56699407  73 KKIVQAGDKDLDGQLDFEEFVH-YLQDHEKK-LRLVFKSLDKKNDGRIDAQEIMQSLRD-LGVKISEQQAEKILKSMD-- 147
Cdd:cd15898  39 KKLFKEVDTNGDGTLTFDEFEElYKSLTERPeLEPIFKKYAGTNRDYMTLEEFIRFLREeQGENVSEEECEELIEKYEpe 118

                ....*....
gi 56699407 148 -KNGTMTID 155
Cdd:cd15898 119 rENRQLSFE 127

mitochondrial carrier protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 56699407  304 LVAGSLAGAIAQSSIYPMEVLKTRMALRKTGQYSgmldcarrilareGVAAFYKGYVPNMLGIIPYAGIDLAVYEtLKNA 383
Cdd:PTZ00168   7 LVTGALSGVIVDAVLYPIDSIKTNIQAKKSFSFS-------------DIKKLYSGILPTLVGTVPASAFFYCFYE-LSKK 72

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 56699407  384 WLQHYAVNSADPGVFvlLACGTMSSTCGQLASYPLALVRTRMQAQASIegapevtmsSLFKHILRTEGAFGLYRGLAPNF 463
Cdd:PTZ00168  73 LLTEYRENISKTNLY--LISTSIAEITACIVRLPFEIVKQNMQVSGNI---------SVLKTIYEITQREGLPSFLGKSY 141

                        170       180
                 ....*....|....*....|..
gi 56699407  464 M----KVIPAVSISYVVYENLK 481
Cdd:PTZ00168 142 FvmivREIPFDCIQYFLWETLK 163

mitochondrial carrier protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 56699407  208 RHLVAGGGAGAVSRTCTAPLDRLKVLMQVHASRSnnmgivggFTQMireggaRSLWRGNGINVLKIAPESAIKFMAYEQI 287
Cdd:PTZ00168   5 HNLVTGALSGVIVDAVLYPIDSIKTNIQAKKSFS--------FSDI------KKLYSGILPTLVGTVPASAFFYCFYELS 70

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 56699407  288 KRLVGSDQETL-RIHERLVAGSLAGAIAQSSIYPMEVLKTRMalrktgQYSG---MLDCARRILAREGVAAFY-KGYVPN 362
Cdd:PTZ00168  71 KKLLTEYRENIsKTNLYLISTSIAEITACIVRLPFEIVKQNM------QVSGnisVLKTIYEITQREGLPSFLgKSYFVM 144

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 56699407  363 MLGIIPYAGIDLAVYETLKNAWLQHYAVNSADPGVFVLLACGTMSSTCGQLASYPLALVRTR--MQAQASIEGAPEVTms 440
Cdd:PTZ00168 145 IVREIPFDCIQYFLWETLKEKAKKDFGKFSKKYPSITSAICGGLAGGIAGFLTTPVDVIKSRqiIYGKSYIETVTEIA-- 222

                        250
                 ....*....|....*...
gi 56699407  441 slfkhilrTEGAFGLYRG 458
Cdd:PTZ00168 223 --------EEGYLTFYKG 232

Penta-EF hand, calcium binding motifs, found in calcium-dependent protease small subunit CAPNS1 and CAPNS2; CAPNS1, also termed calpain small subunit 1 (CSS1), or calcium-activated neutral proteinase small subunit (CANP small subunit), or calcium-dependent protease small subunit (CDPS), or calpain regulatory subunit, is a common 28-kDa regulatory calpain subunit encoded by the calpain small 1 (Capns1, also known as Capn4) gene. It acts as a binding partner to form a heterodimer with the 80 kDa calpain large catalytic subunit and is required in maintaining the activity of calpain. CAPNS1 plays a significant role in tumor progression of human cancer, and functions as a potential therapeutic target in human hepatocellular carcinoma (HCC), nasopharyngeal carcinoma (NPC), glioma, and clear cell renal cell carcinoma (ccRCC). It may be involved in regulating migration and cell survival through binding to the SH3 domain of Ras GTPase-activating protein (RasGAP). It may also modulate Akt/FoxO3A signaling and apoptosis through PP2A. CAPNS1 contains an N-terminal glycine rich domain and a C-terminal PEF-hand domain. CAPNS2, also termed calpain small subunit 2 (CSS2), is a novel tissue-specific 30 kDa calpain small subunit that lacks two oligo-Gly stretches characteristic of the N-terminal Gly-rich domain of CAPNS1. CAPNS2 acts as a chaperone for the calpain large subunit, and appears to be the functional equivalent of CAPNS1. However, CAPNS2 binds the large subunit much more weakly than CAPNS1 and it does not undergo the autolytic conversion typical of CAPNS1.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 56699407  73 KKIVQAGDKDLDGQLDFEEFvHYLQDHEKKLRLVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKSM-DKNGT 151
Cdd:cd16188  46 RSMVAVMDSDTTGKLGFEEF-KYLWNNIKKWQGIYKQFDTDRSGTIGSQELPGAFEAAGFHLNEQLYQMIIRRYsDEDGN 124

                ....
gi 56699407 152 MTID 155
Cdd:cd16188 125 MDFD 128

centrin; Provisional

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 56699407   97 QDHEKKLRLVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKSMDKNGTMTIDWNEWRD 161
Cdd:PTZ00183  13 EDQKKEIREAFDLFDTDGSGTIDPKELKVAMRSLGFEPKKEEIKQMIADVDKDGSGKIDFEEFLD 77

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 56699407  80 DKDLDGQLDFEEFvhylqdheKKL-------RLVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKSMDKNGTM 152
Cdd:cd16181  50 DRDHSGKMGFNEF--------KELwaalnqwKTTFMQYDRDRSGTVEPQELQQAIRSFGYNLSPQALNVIVKRYSKNGRI 121

                ...
gi 56699407 153 TID 155
Cdd:cd16181 122 TFD 124

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 56699407  73 KKIVQAGDKDLDGQLDFEEFVHYLQDHEKK------LRLVFKSLDKKNDGRIDAQEIM---QSLRDLGVKISEQqaEKIL 143
Cdd:cd16227 125 KEMFEAADLNKDGKLDKTEFSAFQHPEEYPhmhpvlIEQTLRDKDKDNDGFISFQEFLgdrAGHEDKEWLLVEK--DRFD 202

                        90
                ....*....|....*
gi 56699407 144 KSMDKNGTMTIDWNE 158
Cdd:cd16227 203 EDYDKDGDGKLDGEE 217

Penta-EF hand, calcium binding motifs, found in sorcin; 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. The up-regulation of sorcin is correlated with a number of cancer types, including colorectal, gastric and breast cancer. It may represent a therapeutic target for reversing tumor multidrug resistance (MDR). Sorcin participates in the regulation of calcium homeostasis in cells and is necessary for the activation of mitosis and cytokinesis. It enhances metastasis and promotes epithelial-to-mesenchymal transition of colorectal cancer. Moreover, sorcin has been implicated in the regulation of intracellular Ca2+ cycling and cardiac excitation-contraction coupling. It displays the anti-apoptotic properties via the modulation of mitochondrial Ca2+ handling in cardiac myocytes. It can target and activate the sarcolemmal Na+/Ca2+ exchanger (NCX1) in cardiac muscle. Meanwhile, sorcin modulates cardiac L-type Ca2+ current by functional interaction with the alpha1C subunit. It also associates with calcium/calmodulin-dependent protein kinase IIdeltaC (CaMKIIdelta(C)) and further modulates ryanodine receptor (RyR) function in cardiac myocytes. Furthermore, sorcin may act as a Ca2+ sensor for glucose-induced nuclear translocation and the activation of carbohydrate-responsive element-binding protein (ChREBP)-dependent genes. As a mitochondrial chaperone TRAP1 interactor, sorcin involves in mitochondrial metabolism through the TRAP1 pathway. In addition, sorcin may regulate the inhibition of type I interferon response in cells through interacting with foot-and-mouth disease virus (FMDV) VP1. Sorcin 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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 56699407  80 DKDLDGQLDFEEFvhylqdheKKLRLV-------FKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKSMDKNGTM 152
Cdd:cd16187  50 DRDMSGTMGFNEF--------KELWAVlngwrqhFISFDSDRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRYSTNGKI 121

                ...
gi 56699407 153 TID 155
Cdd:cd16187 122 TFD 124

centrin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 56699407   73 KKIVQAGDKDLDGQLDFEEFVHYL------QDHEKKLRLVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKSM 146
Cdd:PTZ00183  56 KQMIADVDKDGSGKIDFEEFLDIMtkklgeRDPREEILKAFRLFDDDKTGKISLKNLKRVAKELGETITDEELQEMIDEA 135

                         90
                 ....*....|..
gi 56699407  147 DKNGTMTIDWNE 158
Cdd:PTZ00183 136 DRNGDGEISEEE 147

EF-hand domain;

                          10        20        30
                  ....*....|....*....|....*....|
gi 56699407   102 KLRLVFKSLDKKNDGRIDAQEIMQSLRDLG 131
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSLG 30

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 56699407  69 EQFPKKIVQAGDKDLDGQLDFEEFVHYLQDHEKKLRL---------------VFKSLDKKNDGRIDAQEIMQSLRDL--- 130
Cdd:cd15902  43 AEKKKEFMEKYDENEDGKIEIRELANILPTEENFLLLfrreqplissvefmkIWRKYDTDGSGFIEAKELKGFLKDLllk 122

                        90       100       110
                ....*....|....*....|....*....|...
gi 56699407 131 -GVKISEQQAEK----ILKSMDKNGTMTIDWNE 158
Cdd:cd15902 123 nKKHVSPPKLDEytklILKEFDANKDGKLELDE 155

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 56699407  69 EQFpkkivQAGDKDLDGQLDFEEFVHYLQD-----HEKKLRLVFKSLDKKNDGRIDAQEIMQSLRDL 130
Cdd:cd16202   4 DQF-----RKADKNGDGKLSFKECKKLLKKlnvkvDKDYAKKLFQEADTSGEDVLDEEEFVQFYNRL 65

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
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 56699407 103 LRLVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQQAEKILKSMD---KNGTMTID 155
Cdd:cd16205   2 LKQTFEEADKNGDGLLSIGEILQLMHKLNVNLPRRKVRQMFKEADtddNQGTLDFE 57

Penta-EF hand, calcium binding motifs, found in calpain-9 (CAPN9); CAPN9, also termed digestive tract-specific calpain, or new calpain 4 (nCL-4), or protein CG36, is a calpain large subunit predominantly expressed in gastrointestinal tract. It plays a physiological role in the suppression of tumorigenesis. It acts as an important biomolecule link for the regression of colorectal cancer via intracellular calcium homeostasis. CAPN9 may also play a critical role in lumen formation. Moreover, CAPN9, together with CAPN8, forms an active protease complex, G-calpain, in which both proteins are essential for stability and activity. The G-Calpain has been implicated in gastric mucosal defense. Furthermore, down-regulation of calpain 9 has been linked to hypertensive heart and kidney disease in salt-sensitive Dahl rats. CAPN9 contains 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.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 56699407  73 KKIVQAGDKDLDGQLDFEEFvHYLQDHEKKLRLVFKSLDKKNDGRIDAQEIMQSLRDLGVKISEQ 137
Cdd:cd16192  46 KNIISLMDTSGNGKLGFSEF-KVFWDKLKKWIGLFLKYDADRSGTMSSYELRSALKAAGFQLNNQ 109