EF-hand, calcium binding motif, found in peflin and similar proteins; Peflin, also termed penta-EF hand (PEF) protein with a long N-terminal hydrophobic domain, or penta-EF hand domain-containing protein 1, is a ubiquitously expressed 30-kD PEF protein containing five EF-hand motifs in its C-terminal domain and a longer N-terminal hydrophobic domain (NHB domain) than any other member of the PEF family. The NHB domain harbors nine repeats of a nonapeptide (A/PPGGPYGGP). Peflin may modulate the function of ALG-2 in Ca2+ signaling. It exists only as a heterodimer with ALG-2, and binds two Ca2+ ions through its EF1 and EF3 hands. Its additional EF5 hand is unpaired and does not bind Ca2+ ion but mediates the heterodimerization with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+. In lower vertebrates, peflin may interact with transient receptor potential N (TRPN1), suggesting a potential role of peflin in fast transducer channel adaptation.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937 109 EAYSWFQSVDADHSGYISLKELKQALVNSNWSSFNDETCLMMINMFDKTKSGRIDVAGFSALWKFLQQWRNLFQQYDRDR 188
Cdd:cd16184   1 EVQQWFQAVDRDRSGKISAKELQQALVNGNWSHFNDETCRLMIGMFDKDKSGTIDIYEFQALWNYIQQWKQVFQQFDRDR 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937 189 SGSISSTELQQALSQMGYNLSPQFTQLLVSRYCARSAiPAMQLDCFIKVCTQLQVLTEAFREKDTAVQGNIRLSFEDFVT 268
Cdd:cd16184  81 SGSIDENELHQALSQMGYRLSPQFVQFLVSKYDPRAR-RSLTLDQFIQVCVQLQSLTDAFRQRDTQMTGTITISYEDFLT 159

                ....*.
gi 31980937 269 MTASRM 274
Cdd:cd16184 160 MALLNK 165

EF-hand, calcium binding motif, found in peflin and similar proteins; Peflin, also termed penta-EF hand (PEF) protein with a long N-terminal hydrophobic domain, or penta-EF hand domain-containing protein 1, is a ubiquitously expressed 30-kD PEF protein containing five EF-hand motifs in its C-terminal domain and a longer N-terminal hydrophobic domain (NHB domain) than any other member of the PEF family. The NHB domain harbors nine repeats of a nonapeptide (A/PPGGPYGGP). Peflin may modulate the function of ALG-2 in Ca2+ signaling. It exists only as a heterodimer with ALG-2, and binds two Ca2+ ions through its EF1 and EF3 hands. Its additional EF5 hand is unpaired and does not bind Ca2+ ion but mediates the heterodimerization with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+. In lower vertebrates, peflin may interact with transient receptor potential N (TRPN1), suggesting a potential role of peflin in fast transducer channel adaptation.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937 109 EAYSWFQSVDADHSGYISLKELKQALVNSNWSSFNDETCLMMINMFDKTKSGRIDVAGFSALWKFLQQWRNLFQQYDRDR 188
Cdd:cd16184   1 EVQQWFQAVDRDRSGKISAKELQQALVNGNWSHFNDETCRLMIGMFDKDKSGTIDIYEFQALWNYIQQWKQVFQQFDRDR 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937 189 SGSISSTELQQALSQMGYNLSPQFTQLLVSRYCARSAiPAMQLDCFIKVCTQLQVLTEAFREKDTAVQGNIRLSFEDFVT 268
Cdd:cd16184  81 SGSIDENELHQALSQMGYRLSPQFVQFLVSKYDPRAR-RSLTLDQFIQVCVQLQSLTDAFRQRDTQMTGTITISYEDFLT 159

                ....*.
gi 31980937 269 MTASRM 274
Cdd:cd16184 160 MALLNK 165

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937   114 FQSVDADHSGYISLKELKQALVNSNWS-SFNDETCLMMINMFDKTKSGRIDVAGFSALWK 172
Cdd:pfam13499   8 FKLLDSDGDGYLDVEELKKLLRKLEEGePLSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

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 31980937    113 WFQSVDADHSGYISLKELKQAL 134
Cdd:smart00054   5 AFRLFDKDGDGKIDFEEFKDLL 26

EF-hand, calcium binding motif, found in peflin and similar proteins; Peflin, also termed penta-EF hand (PEF) protein with a long N-terminal hydrophobic domain, or penta-EF hand domain-containing protein 1, is a ubiquitously expressed 30-kD PEF protein containing five EF-hand motifs in its C-terminal domain and a longer N-terminal hydrophobic domain (NHB domain) than any other member of the PEF family. The NHB domain harbors nine repeats of a nonapeptide (A/PPGGPYGGP). Peflin may modulate the function of ALG-2 in Ca2+ signaling. It exists only as a heterodimer with ALG-2, and binds two Ca2+ ions through its EF1 and EF3 hands. Its additional EF5 hand is unpaired and does not bind Ca2+ ion but mediates the heterodimerization with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+. In lower vertebrates, peflin may interact with transient receptor potential N (TRPN1), suggesting a potential role of peflin in fast transducer channel adaptation.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937 109 EAYSWFQSVDADHSGYISLKELKQALVNSNWSSFNDETCLMMINMFDKTKSGRIDVAGFSALWKFLQQWRNLFQQYDRDR 188
Cdd:cd16184   1 EVQQWFQAVDRDRSGKISAKELQQALVNGNWSHFNDETCRLMIGMFDKDKSGTIDIYEFQALWNYIQQWKQVFQQFDRDR 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937 189 SGSISSTELQQALSQMGYNLSPQFTQLLVSRYCARSAiPAMQLDCFIKVCTQLQVLTEAFREKDTAVQGNIRLSFEDFVT 268
Cdd:cd16184  81 SGSIDENELHQALSQMGYRLSPQFVQFLVSKYDPRAR-RSLTLDQFIQVCVQLQSLTDAFRQRDTQMTGTITISYEDFLT 159

                ....*.
gi 31980937 269 MTASRM 274
Cdd:cd16184 160 MALLNK 165

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 31980937 111 YSWFQSVDADHSGYISLKELKQALVNSNWSSFNDETCLMMINMFDKTKSGRIDVAGFSALWKFLQQWRNLFQQYDRDRSG 190
Cdd:cd16183   3 WNVFQRVDKDRSGQISATELQQALSNGTWTPFNPETVRLMIGMFDRDNSGTINFQEFAALWKYITDWQNCFRSFDRDNSG 82

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937 191 SISSTELQQALSQMGYNLSPQFTQLLVSRYcARSAIPAMQLDCFIKVCTQLQVLTEAFREKDTAVQGNIRLSFEDFVTMT 270
Cdd:cd16183  83 NIDKNELKQALTSFGYRLSDQFYDILVRKF-DRQGRGTIAFDDFIQCCVVLQTLTDSFRRYDTDQDGWIQISYEQFLEMV 161

                ....
gi 31980937 271 ASRM 274
Cdd:cd16183 162 FSNV 165

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937 109 EAYSWFQSVDADhSGYISLKELKQALVNSNW----SSFNDETCLMMINMFDKTKSGRIDVAGFSALWKFLQQWRNLFQQY 184
Cdd:cd15897   1 QLRNVFQAVAGD-DGEISATELQQALSNVGWthfdLGFSLETCRSMIAMMDRDHSGKLNFSEFKGLWNYIKAWQEIFRTY 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937 185 DRDRSGSISSTELQQALSQMGYNLSPQFTQLLVSRYCARSAipAMQLDCFIKVCTQLQVLTEAFREKDTAVQGNIRLSFE 264
Cdd:cd15897  80 DTDGSGTIDSNELRQALSGAGYRLSEQTYDIIIRRYDRGRG--NIDFDDFIQCCVRLQRLTDAFRRYDKDQDGQIQVNYD 157

                ....*...
gi 31980937 265 DFVTMTAS 272
Cdd:cd15897 158 EFLQGTMS 165

Penta-EF hand, calcium binding motifs, found in PEF calpain family; The PEF calpain family belongs to the second group of penta-EF hand (PEF) proteins. It includes classical (also called conventional or typical) calpain (referring to a calcium-dependent papain-like enzymes, EC 3.4.22.17) large catalytic subunits (CAPN1, 2, 3, 8, 9, 11, 12, 13, 14) and two calpain small subunits (CAPNS1 and CAPNS2), which are largely confined to animals (metazoans). These PEF-containing are nonlysosomal intracellular calcium-activated intracellular cysteine proteases that play important roles in the degradation or functional modulation in a variety of substrates in response to calcium signalling. The classical mu- and m-calpains are heterodimers consisting of homologous but a distinct (large) L-subunit/chain (CAPN1 or CAPN2) and a common (small) S-subunit/chain (CAPNS1 or CAPNS2). These L-subunits (CAPN1 and CAPN2) and S-subunit CAPNS1 are ubiquitously found in all tissues. Other calpains likely consist of an isolated L-subunit/chain alone. Many of them, such as CAPNS2, CAPN3 (in skeletal muscle, or lens), CAPN8 (in stomach), CAPN9 (in digestive tracts), CAPN11 (in testis), CAPN12 (in follicles), are tissue-specific and have specific functions in distinct organs. The L-subunits of similar structure (called CALPA and B) also have been found in Drosophila melanogaster. The S-subunit seems to have a chaperone-like function for proper folding of the L-subunit. The catalytic L-subunits contain a short N-terminal anchor helix, followed by a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2+-binding penta-EF-hand (PEF) domain. The S-subunits only have the PEF domain following an N-terminal Gly-rich hydrophobic domain. The calpains undergo a rearrangement of the protein backbone upon Ca2+-binding.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937 112 SWFQSVdADHSGYISLKELkQALVNSNWSS-------FNDETCLMMINMFDKTKSGRIDVAGFSALWKFLQQWRNLFQQY 184
Cdd:cd16182   4 ELFEKL-AGEDEEIDAVEL-QKLLNASLLKdmpkfdgFSLETCRSLIALMDTNGSGRLDLEEFKTLWSDLKKWQAIFKKF 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937 185 DRDRSGSISSTELQQALSQMGYNLSPQFTQLLVSRYCARSAIpaMQLDCFIKVCTQLQVLTEAFREKDTAVQGNIRLSFE 264
Cdd:cd16182  82 DTDRSGTLSSYELRKALESAGFHLSNKVLQALVLRYADSTGR--ITFEDFVSCLVRLKTAFETFSALDKKNEGVIPLTLE 159

                ....*.
gi 31980937 265 DFVTMT 270
Cdd:cd16182 160 EWLLLT 165

Penta-EF hand, calcium binding motifs, found in grancalcin; Grancalcin (GCA) is a cytosolic Ca2+-binding protein specifically expressed in neutrophils and monocytes/macrophages. It displays a Ca2+-dependent translocation to granules and plasma membrane upon neutrophil activation, suggesting roles in granule-membrane fusion and degranulation of neutrophils. It may also play a role in the regulation of vesicle/granule exocytosis through the reversible binding of secretory vesicles and plasma membranes upon the presence of calcium. Moreover, GCA is involved in inflammation, as well as in the process of adhesion of neutrophils to fibronectin. It plays a key role in leukocyte-specific functions that are responsible for host defense, and affects the function of integrin receptors on immune cells through binding to L-plastin in the absence of calcium. Furthermore, GCA 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. GCA binds two Ca2+ ions through its EF1 and EF3 hands.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937 111 YSWFQSVdADHSGYISLKELK----QALVNSNWSSFNDETCLMMINMFDKTKSGRIDVAGFSALWKFLQQWRNLFQQYDR 186
Cdd:cd16186   3 WGYFSAV-AGQDGEVDAEELQrcltQSGINGTYTPFSLETCRIMIAMLDRDHTGKMGFNEFKELWAALNAWKQNFMTVDQ 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937 187 DRSGSISSTELQQALSQMGYNLSPQFTQLLVSRYCARSAIpamQLDCFIKVCTQLQVLTEAFREKDTAVQGNIRLSFEDF 266
Cdd:cd16186  82 DRSGTVEPHELRQAIGAMGYRLSPQTLTTIVKRYSKNGRI---YFDDYVACCVKLRALTDFFRRRDHMQQGSVNFIYDDF 158

                ....*.
gi 31980937 267 VTMTAS 272
Cdd:cd16186 159 LQCTMA 164

Penta-EF hand, calcium binding motifs, found in mu-type calpain (CAPN1); CAPN1, also termed calpain-1 80-kDa catalytic subunit, or calpain-1 large subunit, or micromolar-calpain (muCANP), or calcium-activated neutral proteinase 1 (CANP 1), or cell proliferation-inducing gene 30 protein, is a ubiquitously expressed 80-kDa Ca2+-dependent intracellular cysteine protease that 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. The catalytic subunit CAPN1 in complex with a regulatory subunit encoded by CAPNS1 forms a mu-calpain heterodimer. CAPN1 plays a central role in postmortem proteolysis and meat tenderization processes, as well as in regulation of proliferation and survival of skeletal satellite cells. It also acts as a novel regulator in IgE-mediated mast cell activation and could serve as a potential therapeutic target for the management of allergic inflammation. Moreover, CAPN1 is involved in neutrophil motility and functions as a potential target for intervention in inflammatory disease. It also facilitates age-associated aortic wall calcification and fibrosis through the regulation of matrix metalloproteinase 2 activity in vascular smooth muscle cells, and thus plays a role in hypertension and atherosclerosis. The proteolytic cleavage of beta-amyloid precursor protein and tau protein by CAPN1 may be involved in plaque formation. Furthermore, CAPN1 is activated in the brains of individuals with Alzheimer's disease. It is involved in the maintenance of a proliferative neural stem cell pool. The activation and macrophage inflammation of CAPN1 in hypercholesterolemic nephropathy is promoted by nicotinic acetylcholine receptor alpha1 (nAChRalpha1). In addition, CAPN1 displays a functional role in hemostasis, as well as in sickle cell disease.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937 125 ISLKELKQALvNSNWSSFND--------ETCLMMINMFDKTKSGRIDVAGFSALWKFLQQWRNLFQQYDRDRSGSISSTE 196
Cdd:cd16198  16 ISVFELKTIL-NRIISKHKDlrtdgfslESCRSMVNLMDKDGNGKLGLVEFNILWNKIRNYLTIFRKFDLDKSGSMSAYE 94

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 31980937 197 LQQALSQMGYNLSPQFTQLLVSRYCARSAipAMQLDCFIKVCTQLQVLTEAFREKDTAVQGNIRLSFEDFVTMT 270
Cdd:cd16198  95 MRLALESAGFKLNNRLHQVIVARYADPNL--AIDFDNFVCCLVRLETMFRFFKQLDTEETGTIEMDLFEWLQLT 166

Penta-EF hand, calcium binding motifs, found in m-type calpain (CAPN2); CAPN2, also termed millimolar-calpain (m-calpain), or calpain-2 catalytic subunit, or calcium-activated neutral proteinase 2 (CANP 2), or calpain large polypeptide L2, or calpain-2 large subunit, is a ubiquitously expressed 80-kDa Ca2+-dependent intracellular cysteine protease that 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. The catalytic subunit CAPN2 in complex with a regulatory subunit encoded by CAPNS1 forms an m-calpain heterodimer. CAPN2 acts as the key protease responsible for N-methyl-d-aspartic acid (NMDA)-induced cytoplasmic polyadenylation element-binding protein 3 (CPEB3) degradation in neurons. It cleaves several components of the focal adhesion complex, such as FAK and talin, triggering disassembly of the complex at the rear of the cell. The stimulation of CAPN2 activity is required for Golgi antiapoptotic proteins (GAAPs) to promote cleavage of FA kinase (FAK), cell spreading, and enhanced migration. calpain 2 is also involved in the onset of glial differentiation. It regulates proliferation, survival, migration, and tumorigenesis of breast cancer cells through a PP2A-Akt-FoxO-p27(Kip1) signaling cascade. Its expression is associated with response to platinum based chemotherapy, progression-free and overall survival in ovarian cancer. Moreover, CAPN2 may play a role in fundamental mitotic functions, such as the maintenance of sister chromatid cohesion. The activation of CAPN2 plays an essential role in hippocampal synaptic plasticity and in learning and memory. In the eye, CAPN2, together with a lens-specific variant of CAPN3, is responsible for proteolytic cleavages of alpha and beta-crystallin. Overactivated alpha and beta-crystallin can lead to cataract formation. Sometimes, CAPN2 compensates for loss of CAPN1, and both calpain isoforms are involved in AngII-induced aortic aneurysm formation. The main phosphorylation sites in m-calpain are Ser50 and Ser369/Thr370.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937 142 FNDETCLMMINMFDKTKSGRIDVAGFSALWKFLQQWRNLFQQYDRDRSGSISSTELQQALSQMGYNLSPQFTQLLVSRYC 221
Cdd:cd16199  40 FSIETCKIMVDMLDSDGSGKLGLKEFYILWTKIQKYQKIYREIDVDRSGTMNSYEMRKALEEAGFKLPCQLHQVIVARFA 119

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*....
gi 31980937 222 ARSAIpaMQLDCFIKVCTQLQVLTEAFREKDTAVQGNIRLSFEDFVTMT 270
Cdd:cd16199 120 DDDLI--IDFDNFVRCLVRLETLFKIFKQLDPENTGTIELDLISWLSFS 166

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        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937 145 ETCLMMINMFDKTKSGRIDVAGFSALWKFLQQWRNLFQQYDRDRSGSISSTELQQALSQMGYNLSPQFTQLLVSRYcars 224
Cdd:cd16192  43 LSCKNIISLMDTSGNGKLGFSEFKVFWDKLKKWIGLFLKYDADRSGTMSSYELRSALKAAGFQLNNQLLQLIVLRY---- 118

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*...
gi 31980937 225 AIPAMQL--DCFIKVCTQLQVLTEAFREKDTAVQGNIRLSFEDFVTMT 270
Cdd:cd16192 119 ADDYLQIdfDDFLNCLVRLENSFRVFQALDTKNTGEISLNMLEFILLT 166

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 31980937 142 FNDETCLMMINMFDKTKSGRIDVAGFSALWKFLQQWRNLFQQYDRDRSGSISSTELQQALSQMGYNLSPQFTQLLVSRYC 221
Cdd:cd16188  40 FGIDTCRSMVAVMDSDTTGKLGFEEFKYLWNNIKKWQGIYKQFDTDRSGTIGSQELPGAFEAAGFHLNEQLYQMIIRRYS 119

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*....
gi 31980937 222 ARSAipAMQLDCFIKVCTQLQVLTEAFREKDTAVQGNIRLSFEDFVTMT 270
Cdd:cd16188 120 DEDG--NMDFDNFISCLVRLDAMFRAFKSLDKDGTGQIQVNIQEWLQLT 166

Penta-EF hand, calcium binding motifs, found in calpain-8 (CAPN8); CAPN8, also termed new calpain 2 (nCL-2), or stomach-specific M-type calpain, is a calpain large subunit predominantly expressed in the stomach. It appears to be involved in membrane trafficking in the gastric surface mucus cells (pit cells), via its location at the Golgi and interaction with the beta-subunit of coatomer complex (beta-COP) of vesicles derived from the Golgi. Moreover, CAPN8, together with CAPN9, 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. CAPN8 exists as both a monomer and homo-oligomer, but not as a heterodimer with the conventional calpain regulatory subunit (30K). The monomer and homodimer forms predominate. CAPN8 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        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937 142 FNDETCLMMINMFDKTKSGRIDVAGFSALWKFLQQWRNLFQQYDRDRSGSISSTELQQALSQMGYNLSPQFTQLLVSRY- 220
Cdd:cd16191  40 FTINTCREMISLLDTDGTGTLGLVEFRILWMKIQKYLAIYKKVDSDRSGTIDAHEMRNALQEAGFTLNNKIQQSIVQRYa 119

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 31980937 221 CARSAIpamQLDCFIKVCTQLQVLTEAFREKDTAVQGNIRLSFEDFVTMT 270
Cdd:cd16191 120 SNKLTI---NFDGFIACMIRLETLFKMFQLLDKDKSGVVQLSLAEWLCCT 166

Penta-EF hand, calcium binding motifs, found in Drosophila melanogaster calpain-C (CalpC) and similar proteins; CalpC, also termed calcium-activated neutral proteinase homolog C (CANP C), is a catalytically inactive homolog of CalpA and CalpB found in Drosophila. It is strongly expressed in the salivary glands. In contrast with CalpA and CalpB, both of which 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. CalpC is a truncated calpain form missing domain I and about 20 residues from domain II. Moreover, due to all three mutated active site residues (Cys to Arg, His to Val and Asn to Ser), it may not have proteolytic activity.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937 127 LKELKQALVNSNW--SSFNDETCLMMINMFDKTKSGRIDVAGFSALWKFLQQWRNLFQQYDRDRSGSISSTELQQALSQM 204
Cdd:cd16197  21 LQELLEACLPNDYikSCANIDVCRQVVLLMDNSGLGRLKFQDFKDFMCSLKWWQGVFKMHTKEKTGILRAERLRDALEDV 100

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 31980937 205 GYNLSPQFTQLLVSRYCARSAipAMQLDCFIKVCTQLQVLTEAFREKDTAVQGNIRLSFEDFV 267
Cdd:cd16197 101 GFQLNTDVLSILILRYMRKDG--TLRFGDFVSAVLHLTAAFGSFEKKDPLQNGFIKLSLTEWL 161

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937 113 WFQSVDADHSGYISLKELkQALVNSNWSsfndetclMMINMFDKTKSGRIDVAGFSALWKFLQQW------RNLFQQYDR 186
Cdd:COG5126  10 RFDLLDADGDGVLERDDF-EALFRRLWA--------TLFSEADTDGDGRISREEFVAGMESLFEAtvepfaRAAFDLLDT 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937 187 DRSGSISSTELQQALSQMGynlspqftqllvsrycarsaIPAMQLDcfikvctqlqvltEAFREKDTAvqGNIRLSFEDF 266
Cdd:COG5126  81 DGDGKISADEFRRLLTALG--------------------VSEEEAD-------------ELFARLDTD--GDGKISFEEF 125

                .
gi 31980937 267 V 267
Cdd:COG5126 126 V 126

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

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 31980937 106 VDPEAYSWFQSVDADHSGYISLKELKQALVNSNWSsfnDETCLMMINMFDKTKSGRIDVAGFSALWK 172
Cdd:COG5126  67 VEPFARAAFDLLDTDGDGKISADEFRRLLTALGVS---EEEADELFARLDTDGDGKISFEEFVAAVR 130

EF-hand motif found in phosphoinositide phospholipase C delta 4 (PI-PLC-delta4); PI-PLC-delta4, also termed 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-4 (PLCD4), or phospholipase C-delta-4 (PLC-delta-4), is expressed in various tissues with the highest levels detected selectively in the brain, skeletal muscle, testis and kidney. It plays a significant role in cell growth, cell proliferation, tumorigenesis, and in an early stage of fertilization. PI-PLC-delta4 may function as a key enzyme in the regulation of PtdIns(4,5)P2 levels and Ca2+ metabolism in nuclei in response to growth factors, and its expression may be partially regulated by an increase in cytoplasmic Ca2+. Moreover, PI-PLC-delta4 binds glutamate receptor-interacting protein1 (GRIP1) in testis and is required for calcium mobilization essential for the zona pellucida-induced acrosome reaction in sperm. Overexpression or dysregulated expression of PLCdelta4 may initiate oncogenesis in certain tissues through upregulating erbB1/2 expression, extracellular signal-regulated kinase (ERK) signaling pathway, and proliferation in MCF-7 cells. PI-PLC-delta4 contains an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core domain, and a 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. Unlike PI-PLC-delta 1 and 3, a putative nuclear export sequence (NES) located in the EF-hand domain, which may be responsible transporting PI-PLC-delta1 and 3 from the cell nucleus, is not present in PI-PLC-delta4.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937 113 WFQSVDADHSGYISLKELKQALVNSNwSSFNDETCLMMINMFDKTKSGRIDVAGFSALWKFLQQ---WRNLFQQYDRDrS 189
Cdd:cd16219   5 WFQKADKNKDGRMNFKEVRDLLKMMN-VDMNEEHALRLFQMADKSESGTLEGEEFVLFYKALTQredVLKIFQDFSAD-G 82

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|..
gi 31980937 190 GSISSTELQQALS--QMGYNLSPQFTQLLVSRY----CARsAIPAMQLDCFI 235
Cdd:cd16219  83 QKLTLLEFVDFLQqeQLERENTEELAMELIDRYepsdTAK-KLHALSIDGFL 133

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 31980937 118 DADHSGYISLKELKQAL-----VNSNWSSFN--DETCLMMINMFDKTKSGRIDVAGFSALW----KFLQQWRNL------ 180
Cdd:cd15902 100 DTDGSGFIEAKELKGFLkdlllKNKKHVSPPklDEYTKLILKEFDANKDGKLELDEMAKLLpvqeNFLLKFQILgamdlt 179

                        90       100
                ....*....|....*....|....*
gi 31980937 181 -------FQQYDRDRSGSISSTELQ 198
Cdd:cd15902 180 kedfekvFEHYDKDNNGVIEGNELD 204

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 31980937 118 DADHSGYISLKEL-----------KQALVNSNWSSFNDETCLMMiNMFDKTKSGRIDVAGFSALW--------------- 171
Cdd:cd16177   9 DADGNGYIEGKELenffrelerarRGAGVDSKSANFGEKMKEFM-QKYDKNADGRIEMAELAQILpteenfllcfrqhvg 87

                        90       100       110
                ....*....|....*....|....*....|....*.
gi 31980937 172 ---KFLQQWRnlfqQYDRDRSGSISSTELQQALSQM 204
Cdd:cd16177  88 sssEFMEAWR----KYDTDRSGYIEANELKGFLSDL 119

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937  109 EAYSWFqsvDADHSGYISLKELKQAL----VNSNWSSFNDetclmMINMFDKTKSGRIDVAGFSALWK-------FLQQW 177
Cdd:PTZ00184  15 EAFSLF---DKDGDGTITTKELGTVMrslgQNPTEAELQD-----MINEVDADGNGTIDFPEFLTLMArkmkdtdSEEEI 86

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937  178 RNLFQQYDRDRSGSISSTELQQALSQMGYNLSPQftqllvsrycarsaipamQLDCFIkvctqlqvlteafREKDtaVQG 257
Cdd:PTZ00184  87 KEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDE------------------EVDEMI-------------READ--VDG 133

                        170
                 ....*....|....*.
gi 31980937  258 NIRLSFEDFVTMTASR 273
Cdd:PTZ00184 134 DGQINYEEFVKMMMSK 149

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 31980937 118 DADHSGYISLKELK---QALVNSNWSSFND----ETCLMMINMFDKTKSGRIDVAGFSALW----KFLQQWRNL------ 180
Cdd:cd16176  95 DADHSGFIEADELKsflKDLLKKANKPFDEskleEYTHTMLKMFDSNNDGKLGLTEMARLLpvqeNFLLKFQGVkmcgke 174

                        90       100
                ....*....|....*....|....*...
gi 31980937 181 ----FQQYDRDRSGSISSTELQQALSQM 204
Cdd:cd16176 175 fnkiFELYDQDGNGYIDENELDALLKDL 202

EF-hand, calcium binding motif, found in parvalbumin-like EF-hand family; The family includes alpha- and beta-parvalbumins, and a group of uncharacterized calglandulin-like proteins. 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
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 31980937 114 FQSVDADHSGYISLKELKQAL--VNSNWSSFNDETCLMMINMFDKTKSGRIDVAGFSAL 170
Cdd:cd16251  40 FQILDKDKSGFIEEEELKYILkgFSIAGRDLTDEETKALLAAGDTDGDGKIGVEEFATL 98

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 31980937 149 MMINMFDKTKSGRIDVAGFSALWKFL------QQWRNLFQQYDRDRSGSISSTELQQALSQMgyNLSPQFTQLLvSRYCA 222
Cdd:cd15898   4 RQWIKADKDGDGKLSLKEIKKLLKRLnirvseKELKKLFKEVDTNGDGTLTFDEFEELYKSL--TERPELEPIF-KKYAG 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....
gi 31980937 223 RSAiPAMQLDCFIKVC--TQLQVLTEAFREK-----DTAVQgNIRLSFEDFVTM 269
Cdd:cd15898  81 TNR-DYMTLEEFIRFLreEQGENVSEEECEEliekyEPERE-NRQLSFEGFTNF 132

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 31980937 114 FQSVDADHSGYISLKELK---QALVNSNWSSFNDE-------TCLMmiNMFDKTKSGRIDVAGFSALW----KFLQQWRN 179
Cdd:cd15902   5 WMHFDADGNGYIEGKELDsflRELLKALNGKDKTDdevaekkKEFM--EKYDENEDGKIEIRELANILpteeNFLLLFRR 82

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31980937 180 ------------LFQQYDRDRSGSISSTELQ----QALSQMGYNLSPQ----FTQLLVSRYCARSAiPAMQLDCFIKVCT 239
Cdd:cd15902  83 eqplissvefmkIWRKYDTDGSGFIEAKELKgflkDLLLKNKKHVSPPkldeYTKLILKEFDANKD-GKLELDEMAKLLP 161

                       170       180
                ....*....|....*....|....*..
gi 31980937 240 qlqvLTEAFREKDtAVQGNIRLSFEDF 266
Cdd:cd15902 162 ----VQENFLLKF-QILGAMDLTKEDF 183

EF-hand domain;

                          10        20
                  ....*....|....*....|....*.
gi 31980937   109 EAYSWFQSVDADHSGYISLKELKQAL 134
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKAL 26