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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1032278848  36 RIQKLFEFFDNSKLGFLDDTQIEKGLSslsippkyRYASDFLKVCDSNRDGRVDYQEFRRYMDAKELELY-----KIFQA 110
Cdd:COG5126     6 KLDRRFDLLDADGDGVLERDDFEALFR--------RLWATLFSEADTDGDGRISREEFVAGMESLFEATVepfarAAFDL 77

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1032278848 111 IDIEHNGDICPAELWEALdkAGIKIKDEELASFMEHVDKDNNGIITFEEWRDFL 164
Cdd:COG5126    78 LDTDGDGKISADEFRRLL--TALGVSEEEADELFARLDTDGDGKISFEEFVAAV 129

Mitochondrial carrier protein;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1032278848 291 GDIGTSGRLLAGGLAGAVAQTAIYPMDLVKTRLQT--FVSEVGTPKLWKLTKDIWIQEGPRAFYRGLCPSLIGIIPYAGI 368
Cdd:pfam00153   1 SELSFLASLLAGGIAGAIAVTVTYPLDVVKTRLQVqgGSGKSKGRGILDCFKKIYKEEGIRGLYKGLLPNLLRVAPAAAI 80

                          90
                  ....*....|.
gi 1032278848 369 DLAAYETLKDL 379
Cdd:pfam00153  81 YFGTYETLKRL 91

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 1032278848 103 ELYKIFQAIDIEHNGDICPAELWEALDKAGIKIKDEELASFMEHVDKDNNGIITFEEWRDFL 164
Cdd:cd00051     1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELM 62

EF-hand domain pair;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1032278848 103 ELYKIFQAIDIEHNGDICPAELWEALDKA--GIKIKDEELASFMEHVDKDNNGIITFEE 159
Cdd:pfam13499   3 KLKEAFKLLDSDGDGYLDVEELKKLLRKLeeGEPLSDEEVEELFKEFDLDKDGRISFEE 61

Mitochondrial carrier protein;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1032278848 291 GDIGTSGRLLAGGLAGAVAQTAIYPMDLVKTRLQT--FVSEVGTPKLWKLTKDIWIQEGPRAFYRGLCPSLIGIIPYAGI 368
Cdd:pfam00153   1 SELSFLASLLAGGIAGAIAVTVTYPLDVVKTRLQVqgGSGKSKGRGILDCFKKIYKEEGIRGLYKGLLPNLLRVAPAAAI 80

                          90
                  ....*....|.
gi 1032278848 369 DLAAYETLKDL 379
Cdd:pfam00153  81 YFGTYETLKRL 91

Mitochondrial carrier protein;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1032278848 390 EPGPLIQLGCGMTSGALGASCVYPLQVIRTRMQADSSKT-----SMGQEFLKTLRGEGLKGFYRGIFPNFFKVIPSASIS 464
Cdd:pfam00153   2 ELSFLASLLAGGIAGAIAVTVTYPLDVVKTRLQVQGGSGkskgrGILDCFKKIYKEEGIRGLYKGLLPNLLRVAPAAAIY 81

                          90
                  ....*....|.
gi 1032278848 465 YLVYEAMKKNL 475
Cdd:pfam00153  82 FGTYETLKRLL 92

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 1032278848 103 ELYKIFQAIDIEHNGDICPAELWEALDKAGIKIKDEELASFMEHVDKDNNGIITFEEWRDFL 164
Cdd:cd00051     1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELM 62

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 1032278848  36 RIQKLFEFFDNSKLGFLDDTQIEKGLSSLSIPPKYRYASDFLKVCDSNRDGRVDYQEFRR-YMDAKEL-ELYKIFQAIDI 113
Cdd:cd15898     1 WLRRQWIKADKDGDGKLSLKEIKKLLKRLNIRVSEKELKKLFKEVDTNGDGTLTFDEFEElYKSLTERpELEPIFKKYAG 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1032278848 114 EHNGDICPAELWEAL-DKAGIKIKDEELASFMEHVDKD-NNGIITFEEWRDFLL 165
Cdd:cd15898    81 TNRDYMTLEEFIRFLrEEQGENVSEEECEELIEKYEPErENRQLSFEGFTNFLL 134

calmodulin; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1032278848  41 FEFFDNSKLGFLDDTQIEKGLSSLSIPPKYRYASDFLKVCDSNRDGRVDYQEFRRYMDAK------ELELYKIFQAIDIE 114
Cdd:PTZ00184   17 FSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLMARKmkdtdsEEEIKEAFKVFDRD 96

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1032278848 115 HNGDICPAELWEALDKAGIKIKDEELASFMEHVDKDNNGIITFEEW 160
Cdd:PTZ00184   97 GNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEF 142

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 1032278848  18 TMEHVLVA-LRETKEKREIRIQKLFEFFDNSKLGFLDDTQIEKGLSSL-------SIPPKYR-YASDFLKVCDSNRDGRV 88
Cdd:cd15902    72 TEENFLLLfRREQPLISSVEFMKIWRKYDTDGSGFIEAKELKGFLKDLllknkkhVSPPKLDeYTKLILKEFDANKDGKL 151

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1032278848  89 DYQEFRRYMDAKELELY----------------KIFQAIDIEHNGDICPAELwEAL-------DKAGIKIKDEELA--SF 143
Cdd:cd15902   152 ELDEMAKLLPVQENFLLkfqilgamdltkedfeKVFEHYDKDNNGVIEGNEL-DALlkdllekNKADIDKPDLENFrdAI 230

                         170       180
                  ....*....|....*....|.
gi 1032278848 144 MEHVDKDNNGIITFEEWRDFL 164
Cdd:cd15902   231 LRACDKNKDGKIQKTELALFL 251

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1032278848  38 QKLFEFFDNSKLGFLDDTQIEKGLSSLSIPPKYRYASDFLKVCDSNRDGRVDYQEFRRYMDAKEL---ELYKIFQAIDIE 114
Cdd:COG5126    36 ATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISADEFRRLLTALGVseeEADELFARLDTD 115

                          90
                  ....*....|....*.
gi 1032278848 115 HNGDICPAELWEALDK 130
Cdd:COG5126   116 GDGKISFEEFVAAVRD 131

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 1032278848  37 IQKLFEFFDNSKLGFLDDTQIEKGLSSLSIPPKYRYASDFLKVCDSNRDGRVDYQEFR---RYMdakeLELYKIFQAIDI 113
Cdd:cd16185     2 LRQWFRAVDRDRSGSIDVNELQKALAGGGLLFSLATAEKLIRMFDRDGNGTIDFEEFAalhQFL----SNMQNGFEQRDT 77

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1032278848 114 EHNGDICPAELWEALDKAGIKIKDEELASFMEHVDKDNNGIITFEEW 160
Cdd:cd16185    78 SRSGRLDANEVHEALAASGFQLDPPAFQALFRKFDPDRGGSLGFDDY 124

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 1032278848  36 RIQKLFEFFDNSKLGFLDDTQIEKGLSSLSIPPKYRYASDFLKVCDSNRDGRVDYQEFRRYM 97
Cdd:cd00051     1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELM 62

Penta-EF hand, calcium binding motifs, found in calpain-13 (CAPN13), calpain-14 (CAPN14), and similar proteins; CAPN13, also termed calcium-activated neutral proteinase 13 (CANP 13), a 63.6 kDa calpain large subunit that exhibits a restricted tissue distribution with low levels of expression detected only in human testis and lung. In calpain family, CAPN13 is most closely related to calpain-14 (CAPN14). CAPN14, also termed calcium-activated neutral proteinase 14 (CANP 14), is a 76.7 kDa calpain large subunit that is most highly expressed in the oesophagus. Its expression and calpain activity can be induced by IL-13. Both CAPN13 and CAPN14 contain 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        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1032278848  81 DSNRDGRVDYQEFRRYMdaKELELYK-IFQAIDIEHNGDICPAELWEALDKAGIKIkDEELASFMEHVDKDNNGIITFEe 159
Cdd:cd16195    53 DLSVNGRLSLEEFSRLW--KKLRKYKdIFQKADVSKSGFLSLSELRNAIQAAGIRV-SDDLLNLMALRYGDSSGRISFE- 128

                  ....*..
gi 1032278848 160 wrDFLLL 166
Cdd:cd16195   129 --SFICL 133

mitochondrial carrier protein; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1032278848 208 LLAGGIAGAVSRTATAPLDRLKVALQVQrTNLGVVPTIKKIWREDKLLGFFrGNG--LNVAKVAPESAIKFAAYEMLKPi 285
Cdd:PTZ00168   88 LISTSIAEITACIVRLPFEIVKQNMQVS-GNISVLKTIYEITQREGLPSFL-GKSyfVMIVREIPFDCIQYFLWETLKE- 164

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1032278848 286 igGADGDIGTSGRL-------LAGGLAGAVAQTAIYPMDLVKTRL----QTFVSEVgtpklwkltKDIwIQEGPRAFYRG 354
Cdd:PTZ00168  165 --KAKKDFGKFSKKypsitsaICGGLAGGIAGFLTTPVDVIKSRQiiygKSYIETV---------TEI-AEEGYLTFYKG 232

                  ..
gi 1032278848 355 LC 356
Cdd:PTZ00168  233 CC 234

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 1032278848  27 RETKEKREIRIQKLFEFFDNSKLGFLDDTQIEKGLSSLSIPPK----------YRYASDFLKVCDSNRDGRVDYQEFRRY 96
Cdd:cd16179    87 RDNPLDSSVEFMKVWREYDKDNSGYIEADELKNFLKHLLKEAKrdndvsedklIEYTDTILQLFDRNKDGKLQLSEMARL 166

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1032278848  97 MDAKE----------------LELYKIFQAIDIEHNGDICPAELW----EALDKAGIKIKDEELASF----MEHVDKDNN 152
Cdd:cd16179   167 LPVKEnflcrpifkgagkltrEDIDRVFALYDRDNNGTIENEELTgflkDLLELVQEDYDEQDLEEFkeiiLRGWDFNND 246

                         170
                  ....*....|...
gi 1032278848 153 GIITFEEWRDFLL 165
Cdd:cd16179   247 GKISRKELTMLLL 259

EF-hand, extracellular calcium-binding (EC) motif, found in secreted protein acidic and rich in cysteine (SPARC)-like proteins; The SPARC protein family represents a diverse group of proteins that share a follistatin-like (FS) domain and an extracellular calcium-binding (EC) domain with two EF-hand motifs. It includes SPARC (for secreted protein acidic and rich in cysteine, also termed osteonectin/ON, or basement-membrane protein 40/BM-40), SPARC-like protein 1 (for secreted protein, acidic and rich in cysteines-like 1/ SPARCL1, also termed high endothelial venule protein/Hevi, or MAST 9, or SC-1, or RAGS-1, or QR1, or ECM 2), testicans 1, 2, and 3 (also termed SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycans, or SPOCK), secreted modular calcium-binding protein SMOC-1 (also termed SPARC-related modular calcium-binding protein 1) and SMOC-2 (also termed SPARC-related modular calcium-binding protein 2, or smooth muscle-associated protein 2/SMAP-2), follistatin-related protein 1 (FRP-1, also termed follistatin-like protein 1/fstl-1, TSC-36/Flik, TGF-beta inducible protein). The SPARC proteins have been implicated in modulating cell interaction with the extracellular milieu, including regulation of extracellular matrix assembly and deposition, counter-adhesion, effects on extracellular protease activity, and modulation of growth factor/cytokine signaling pathways, as well as in development and disease.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1032278848  37 IQKLFEFFDNSKLGFLDDTQIEKGLSSLsIPPKyRYASDFLKVCDSNRDGRVDYQEF 93
Cdd:cd00252    47 AQWEFDNLDNNKDGKLDKRELAPFRAPL-MPLE-HCARGFFESCDLNKDKKISLQEW 101

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 1032278848 139 ELASFMEHVDKDNNGIITFEEWRDFL 164
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELL 26

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1032278848 103 ELYKIFQAIDiEHNGDICPAELWEALDKAGIKIKD-----EELASFMEHVDKDNNGIITFEEWRD 162
Cdd:cd15897     1 QLRNVFQAVA-GDDGEISATELQQALSNVGWTHFDlgfslETCRSMIAMMDRDHSGKLNFSEFKG 64

Penta-EF hand, calcium binding motifs, found in Drosophila melanogaster calpain-A (CalpA), calpain-B (CalpB), and similar proteins; The family contains two calpains that have been found in Drosophila, CalpA and CalpB. CalpA, also termed calcium-activated neutral proteinase A (CANP A), or calpain-A catalytic subunit, is a Drosophila calpain homolog specifically expressed in a few neurons in the central nervous system, in scattered endocrine cells in the midgut, and in blood cells. CalpB, also termed calcium-activated neutral proteinase B (CANP B), contains calpain-B catalytic subunit 1 and calpain-B catalytic subunit 2. Both CalpA and CalpB are closely related to that of vertebrate calpains, and they share similar domain architecture, which consists of four domains: the N-terminal domain I, the catalytic domain II carrying the three active site residues, Cys, His and Asn, the Ca2+-regulated phospholipid-binding domain III, and penta-EF-hand Ca2+-binding domain IV. Besides, CalpA and CalpB display some distinguishing structural features that are not found in mammalian typical calpains. CalpA harbors a 76 amino acid long hydrophobic stretch inserted in domain IV, which may be involved in membrane attachment of this enzyme. CalpB has an unusually long N-terminal tail of 224 amino acids, which belongs to the class of intrinsically unstructured proteins (IUP) and may become ordered upon binding to target protein(s). Moreover, they do not need small regulatory subunits for their catalytic activity, and their proteolytic function is not regulated by an intrinsic inhibitor as the Drosophila genome contains neither regulatory subunit nor calpastatin orthologs. As a result, they may exist as a monomer or perhaps as a homo- or heterodimer together with a second large subunit. Furthermore, both CalpA and CalpB are dispensable for viability and fertility and do not share vital functions during Drosophila development. Phosphatidylinositol 4,5-diphosphate, phosphatidylinositol 4-monophosphate, phosphatidylinositol, and phosphatidic acid can stimulate the activity and the rate of activation of CalpA, but not CalpB. Calpain A modulates Toll responses by limited Cactus/IkappaB proteolysis. CalpB directly interacts with talin, an important component of the focal adhesion complex, and functions as an important modulator in border cell migration within egg chambers, which may act via the digestion of talin. CalpB can be phosphorylated by cAMP-dependent protein kinase (protein kinase A, PKA; EC 2.7.11.11) at Ser240 and Ser845, as well as by mitogen-activated protein kinase (ERK1 and ERK2; EC 2.7.11.24) at Thr747. The activation of the ERK pathway by extracellular signals results in the phosphorylation and activation of calpain B. In Schneider cells (S2), calpain B was mainly in the cytoplasm and upon a rise in Ca2+ the enzyme adhered to intracellular membranes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1032278848  81 DSNRDGRVDYQEFRRYMDakELELYK-IFQAIDIEHNGDICPAELWEALDKAGIKIKDEELASF-MEHVDKDNNgiITFE 158
Cdd:cd16196    51 DVDRSGKLGFEEFKKLWE--DLRSWKrVFKLFDTDGSGSFSSFELRNALNSAGFRLSNATLNALvLRYSNKDGR--ISFD 126

                  ....*...
gi 1032278848 159 ewrDFLLL 166
Cdd:cd16196   127 ---DFIMC 131

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).

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gi 1032278848  37 IQKLFEFFDNSKLGFLDDTQIEKGLSSLSipPKYRYASD-----FLKVCDSNRDGRVDYQEFRRYMDA 99
Cdd:cd16255    36 VKKVFEIIDQDKSGFIEEEELKLFLQNFS--SGARELTDaetkaFLKAGDSDGDGKIGVEEFQALVKA 101

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+.

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gi 1032278848 103 ELYKIFQAIDIEHNGDICPAELWEALDKAGIKIKDEELASFMEHV-DKDNNGIITFEE 159
Cdd:cd16180     1 ELRRIFQAVDRDRSGRISAKELQRALSNGDWTPFSIETVRLMINMfDRDRSGTINFDE 58