centrin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4757902    16 RKRMSPKPELTEEQKQEIREAFDLFDADGTGTIDVKELKVAMRALGFEPKKEEIKKMISEIDKEGTGKMNFGDFLTVMTQ 95
Cdd:PTZ00183   2 RKRRSERPGLTEDQKKEIREAFDLFDTDGSGTIDPKELKVAMRSLGFEPKKEEIKQMIADVDKDGSGKIDFEEFLDIMTK 81

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 4757902    96 KMSEKDTKEEILKAFKLFDDDETGKISFKNLKRVAKELGENLTDEELQEMIDEADRDGDGEVSEQEFLRIMKKTSLY 172
Cdd:PTZ00183  82 KLGERDPREEILKAFRLFDDDKTGKISLKNLKRVAKELGETITDEELQEMIDEADRNGDGEISEEEFYRIMKKTNLF 158

centrin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4757902    16 RKRMSPKPELTEEQKQEIREAFDLFDADGTGTIDVKELKVAMRALGFEPKKEEIKKMISEIDKEGTGKMNFGDFLTVMTQ 95
Cdd:PTZ00183   2 RKRRSERPGLTEDQKKEIREAFDLFDTDGSGTIDPKELKVAMRSLGFEPKKEEIKQMIADVDKDGSGKIDFEEFLDIMTK 81

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 4757902    96 KMSEKDTKEEILKAFKLFDDDETGKISFKNLKRVAKELGENLTDEELQEMIDEADRDGDGEVSEQEFLRIMKKTSLY 172
Cdd:PTZ00183  82 KLGERDPREEILKAFRLFDDDKTGKISLKNLKRVAKELGETITDEELQEMIDEADRNGDGEISEEEFYRIMKKTNLF 158

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 4757902  105 EILKAFKLFDDDETGKISFKNLKRVAKELGENLTDEELQEMIDEADRDGDGEVSEQEFLRIMK 167
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

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 4757902     141 ELQEMIDEADRDGDGEVSEQEFLRIMKKT 169
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

centrin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4757902    16 RKRMSPKPELTEEQKQEIREAFDLFDADGTGTIDVKELKVAMRALGFEPKKEEIKKMISEIDKEGTGKMNFGDFLTVMTQ 95
Cdd:PTZ00183   2 RKRRSERPGLTEDQKKEIREAFDLFDTDGSGTIDPKELKVAMRSLGFEPKKEEIKQMIADVDKDGSGKIDFEEFLDIMTK 81

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 4757902    96 KMSEKDTKEEILKAFKLFDDDETGKISFKNLKRVAKELGENLTDEELQEMIDEADRDGDGEVSEQEFLRIMKKTSLY 172
Cdd:PTZ00183  82 KLGERDPREEILKAFRLFDDDKTGKISLKNLKRVAKELGETITDEELQEMIDEADRNGDGEISEEEFYRIMKKTNLF 158

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4757902   27 EEQKQEIREAFDLFDADGTGTIDVKELKVAMRALgfepkkeeIKKMISEIDKEGTGKMNFGDFLTVMTqKMSEKDTKEEI 106
Cdd:COG5126   1 DLQRRKLDRRFDLLDADGDGVLERDDFEALFRRL--------WATLFSEADTDGDGRISREEFVAGME-SLFEATVEPFA 71

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 4757902  107 LKAFKLFDDDETGKISFKNLKRVAKELGenLTDEELQEMIDEADRDGDGEVSEQEFLRIMKK 168
Cdd:COG5126  72 RAAFDLLDTDGDGKISADEFRRLLTALG--VSEEEADELFARLDTDGDGKISFEEFVAAVRD 131

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 4757902   32 EIREAFDLFDADGTGTIDVKELKVAMRALGFEPKKEEIKKMISEIDKEGTGKMNFGDFLTVMT 94
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

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 4757902   32 EIREAFDLFDADGTGTIDVKELKVAMRALGFEPKKEEIKKMISEIDKEGTGKMNFGD------FLTVMTQkmsekdtkee 105
Cdd:cd16185   1 ELRQWFRAVDRDRSGSIDVNELQKALAGGGLLFSLATAEKLIRMFDRDGNGTIDFEEfaalhqFLSNMQN---------- 70

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 4757902  106 ilkAFKLFDDDETGKISFKNLKRVAKELGENLTDEELQEMIDEADRDGDGEVSEQEFLRI 165
Cdd:cd16185  71 ---GFEQRDTSRSGRLDANEVHEALAASGFQLDPPAFQALFRKFDPDRGGSLGFDDYIEL 127

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 4757902    103 KEEILKAFKLFDDDETGKISFKNLKRVAK--ELGENLTDEELQEMIDEADRDGDGEVSEQEFLRIMK 167
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRklEEGEPLSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

Penta-EF hand, calcium binding motifs, found in Group I PEF proteins; The family corresponds to Group I PEF proteins that have been found not only in higher animals but also in lower animals, plants, fungi and protists. Group I PEF proteins include apoptosis-linked gene 2 protein (ALG-2), peflin and similar proteins. ALG-2, also termed programmed cell death protein 6 (PDCD6), is a widely expressed calcium-binding modulator protein associated with cell proliferation and death, as well as cell survival. It forms a homodimer in the cell or a heterodimer with its closest paralog peflin. Among the PEF proteins, ALG-2 can bind three Ca2+ ions through its EF1, EF3, and EF5 hands, where it is unique in that its EF5 hand binds Ca2+ ion in a canonical coordination. Peflin is a ubiquitously expressed 30-kD PEF protein containing five EF-hand motifs in its C-terminal domain and a longer N-terminal hydrophobic domain (NHB domain) than any other member of the PEF family. The NHB domain harbors nine repeats of a nonapeptide (A/PPGGPYGGP). Peflin may modulate the function of ALG-2 in Ca2+ signaling. It exists only as a heterodimer with ALG-2, and binds two Ca2+ ions through its EF1 and EF3 hands. Its additional EF5 hand is unpaired and does not bind Ca2+ ion but mediates the heterodimerization with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4757902   34 REAFDLFDADGTGTIDVKELKVAMRALGFEPKKEEIKKMISEIDKEGTGKMNFGDFLTVMT--QKMSEkdtkeeilkAFK 111
Cdd:cd16180  70 RRLFRRFDRDRSGSIDFNELQNALSSFGYRLSPQFVQLLVRKFDRRRRGSISFDDFVEACVtlKRLTD---------AFR 140

                        90
                ....*....|..
gi 4757902  112 LFDDDETGKISF 123
Cdd:cd16180 141 KYDTNRTGYATI 152

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 4757902   31 QEIREAFDLFDADGTGTIDVKELKVAMRALGFEPKKEEIKKMISEIDKEGTGKMNFGDFLT--VMTQKMSEkdtkeeilk 108
Cdd:cd16183  67 TDWQNCFRSFDRDNSGNIDKNELKQALTSFGYRLSDQFYDILVRKFDRQGRGTIAFDDFIQccVVLQTLTD--------- 137

                        90
                ....*....|....*
gi 4757902  109 AFKLFDDDETGKISF 123
Cdd:cd16183 138 SFRRYDTDQDGWIQI 152

calmodulin; Provisional

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 4757902    30 KQEIREAFDLFDADGTGTIDVKELKVAMRALGFEPKKEEIKKMISEIDKEGTGKMNFGDFLTVMTQK 96
Cdd:PTZ00184  83 EEEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMMMSK 149

EF-hand, calcium binding motif, found in mitochondrial calcium uptake proteins MICU1, MICU2, MICU3, and similar proteins; This family includes mitochondrial calcium uptake protein MICU1 and its two additional paralogs, MICU2 and MICU3. MICU1 localizes to the inner mitochondrial membrane (IMM). It functions as a gatekeeper of the mitochondrial calcium uniporter (MCU) and regulates MCU-mediated mitochondrial Ca2+ uptake, which is essential for maintaining mitochondrial homoeostasis. MICU1 and MICU2 are physically associated within the uniporter complex and are co-expressed across all tissues. They may play non-redundant roles in the regulation of the mitochondrial calcium uniporter. At present, the precise molecular function of MICU2 and MICU3 remain unclear. MICU2 may play possible roles in Ca2+ sensing and regulation of MCU, calcium buffering with a secondary impact on transport or assembly and stabilization of MCU. MICU3 likely has a role in mitochondrial calcium handling. All members in this family contains an N-terminal mitochondrial targeting sequence (MTS) as well as two evolutionarily conserved canonical Ca2+-binding EF-hands separated by a long stretch of residues predicted to form alpha-helices.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4757902   36 AFDLFDADGTGTIDVKELKVAMRAL----------GFEPKKEEIKKMISEI------DKEGTGKMNFGDFLTVMTQKMSE 99
Cdd:cd15900   5 AFKMFDLDGDGELDKEEFNKVQSIIrsqtsvgqrhRDHTNGESTKLGMNSTlaryffGKDGKQKLSIEKFLEFQENLQEE 84

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 4757902  100 KDTKEEILKAFKLFDDDetgkISFKNLKRVAKEL-GENLTDEELQEMIDEADRDGDGEVSEQEFLRIMK 167
Cdd:cd15900  85 IDDVDTALTFYHLAGAS----IDRKTFKRAAKVVaGVELSDHVVDVVFTIFDEDGDGILSHKEFISVMK 149

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 4757902   27 EEQKQEIREAFDLFDADGTGTIDVKELKVAMRALGFEPKK--------EEIKKMISEIDKEGTGKMNFGD---------- 88
Cdd:cd15902  86 LISSVEFMKIWRKYDTDGSGFIEAKELKGFLKDLLLKNKKhvsppkldEYTKLILKEFDANKDGKLELDEmakllpvqen 165

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4757902   89 FLTVMTQKMSEKDTKEEILKAFKLFDDDETGKISFKNLKRVAKELGE-NLTDEELQEM-------IDEADRDGDGEVSEQ 160
Cdd:cd15902 166 FLLKFQILGAMDLTKEDFEKVFEHYDKDNNGVIEGNELDALLKDLLEkNKADIDKPDLenfrdaiLRACDKNKDGKIQKT 245

                .
gi 4757902  161 E 161
Cdd:cd15902 246 E 246

EF-hand domain;

                          10        20        30
                  ....*....|....*....|....*....|
gi 4757902     32 EIREAFDLFDADGTGTIDVKELKVAMRALG 61
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSLG 30

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 4757902   31 QEIREAFDLFDADGTGTIDVKELKVAMRALGFEPKKEEIKKMISEIDKEGTGKMNFGDF--LTVMTQKMSEkdtkeeilk 108
Cdd:cd16184  67 QQWKQVFQQFDRDRSGSIDENELHQALSQMGYRLSPQFVQFLVSKYDPRARRSLTLDQFiqVCVQLQSLTD--------- 137

                        90
                ....*....|...
gi 4757902  109 AFKLFDDDETGKI 121
Cdd:cd16184 138 AFRQRDTQMTGTI 150

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 4757902     141 ELQEMIDEADRDGDGEVSEQEFLRIMKKT 169
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

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
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 4757902  106 ILKAFKLFDDDETGKISFKNLKRVAKELGENLTDEELQEMIDEADRDGDGEVSEQEFLRIMKK 168
Cdd:cd15898   2 LRRQWIKADKDGDGKLSLKEIKKLLKRLNIRVSEKELKKLFKEVDTNGDGTLTFDEFEELYKS 64

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 4757902   37 FDLFDADGTGTIDVKELKVA-MRALGFEPKKEEIKKMISEIDKEGTGKMNFGDF---LTVMTQKMSekdtkeeilkAFKL 112
Cdd:cd16184   6 FQAVDRDRSGKISAKELQQAlVNGNWSHFNDETCRLMIGMFDKDKSGTIDIYEFqalWNYIQQWKQ----------VFQQ 75

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 4757902  113 FDDDETGKISFKNLKRVAKELGENLTDEELQEMIDEADRDGDGEVSEQEF 162
Cdd:cd16184  76 FDRDRSGSIDENELHQALSQMGYRLSPQFVQFLVSKYDPRARRSLTLDQF 125

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 4757902      32 EIREAFDLFDADGTGTIDVKELKVAMRAL 60
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

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 4757902    141 ELQEMIDEADRDGDGEVSEQEFLRIMKKT 169
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLKKL 29

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 4757902     32 EIREAFDLFDADGTGTIDVKELKVAMRAL 60
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLKKL 29

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 4757902   34 REAFDLFDADGTGTIDVKELKVAMRALGFEPKKEEIKKMISEIDKegTGKMNFGDF------LTVMTQKMSEKDT 102
Cdd:cd16181  73 KTTFMQYDRDRSGTVEPQELQQAIRSFGYNLSPQALNVIVKRYSK--NGRITFDDFvacavrLRALTDRFRRRDT 145

EF-hand, calcium binding motif, found in reticulocalbin-2 (RCN2); RCN2, also termed calcium-binding protein ERC-55, or E6-binding protein (E6BP), or TCBP-49, is an endoplasmic reticulum resident low-affinity Ca2+-binding protein that has been implicated in immunity, redox homeostasis, cell cycle regulation and coagulation. It is associated with tumorigenesis, in particular with transformation of cells of the cervix induced by human papillomavirus (HPV), through binding to human papillomavirus (HPV) E6 oncogenic protein. It specifically interacts with vitamin D receptor among nuclear receptors. RCN2 contains an N-terminal signal sequence followed by six copies of the EF-hand Ca2+-binding motif, and 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 4757902   69 IKKMISEIDKEGTGKMNFGDFLTVMTQKMSEKDTKE----EILKAFKLFDDDETGKISFKNLKRVAKELGENLTDEELQE 144
Cdd:cd16224 163 IQEALEEHDKDGDGFISLEEFLGDYRKDPTANEDPEwiivEKDRFVNDYDKDNDGKLDPQELLPWVVPNNYGIAQEEALH 242

                        90
                ....*....|....*....
gi 4757902  145 MIDEADRDGDGEVSEQEFL 163
Cdd:cd16224 243 LIDEMDLNGDGRLSEEEIL 261

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 4757902   41 DADGTGTIDVKELKVAMRALGFEPKKEE-IKKMISEIDKEGTGKMNFGDFLTVMtqkmsekdtK--EEILKAFKLFDDDE 117
Cdd:cd16183  10 DKDRSGQISATELQQALSNGTWTPFNPEtVRLMIGMFDRDNSGTINFQEFAALW---------KyiTDWQNCFRSFDRDN 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....
gi 4757902  118 TGKISFKNLKRVAKELGENLTDEELQEMIDEADRDGDGEVSEQEFLR--IMKKT 169
Cdd:cd16183  81 SGNIDKNELKQALTSFGYRLSDQFYDILVRKFDRQGRGTIAFDDFIQccVVLQT 134

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 4757902   46 GTIDVKELKVAMRALGF----EP-KKEEIKKMISEIDKEGTGKMNFGDFLTVMTQKMSEKDTkeeilkaFKLFDDDETGK 120
Cdd:cd16181  14 GQIDADELQRCLTQSGIsgnyQPfSLETCRLMIAMLDRDHSGKMGFNEFKELWAALNQWKTT-------FMQYDRDRSGT 86

                        90       100
                ....*....|....*....|....*.
gi 4757902  121 ISFKNLKRVAKELGENLTDEELQEMI 146
Cdd:cd16181  87 VEPQELQQAIRSFGYNLSPQALNVIV 112

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 4757902   36 AFDLFDADGTGTIDVKELKVAMRALGFEPKKEEIKKMISEI-DKEgtGKMNFGDFLTVMT--QKMSEKdtkeeilkaFKL 112
Cdd:cd16196  76 VFKLFDTDGSGSFSSFELRNALNSAGFRLSNATLNALVLRYsNKD--GRISFDDFIMCAVklKTMFEI---------FKE 144

                        90
                ....*....|.
gi 4757902  113 FDDDETGKISF 123
Cdd:cd16196 145 KDPRGGGRATF 155

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

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 4757902  100 KDTKEEILKAFKLFDDDETGKISFKNLKRVAKEL---GENLTDEELQEMIDEADRDGDGEVSEQEFLRIMK 167
Cdd:cd16255  30 KKSADDVKKVFEIIDQDKSGFIEEEELKLFLQNFssgARELTDAETKAFLKAGDSDGDGKIGVEEFQALVK 100

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 4757902   35 EAFDLFDADGTGTIDVKELKVAMRALGFEPKK------EEIKKMISEIDKEGTGKMNFGDFLTVMTQKMS-------EKD 101
Cdd:cd16176   3 EIWHHYDNDGNGYIEGKELQSFIQELQQARKKaglelsDQMKAFVDQYGQSTDGKIGIVELAQILPTEENfllffrqQLK 82

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 4757902  102 TKEEILKAFKLFDDDETGKISFKNLKRVAKEL--------GENLTDEELQEMIDEADRDGDGEVSEQEFLRIM 166
Cdd:cd16176  83 SSEEFMQTWRKYDADHSGFIEADELKSFLKDLlkkankpfDESKLEEYTHTMLKMFDSNNDGKLGLTEMARLL 155

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 4757902   32 EIREAFDlfDADGT-GTIDVKELK-----VAMRALGFEP-KKEEIKKMISEIDKEGTGKMNFGDFLTVMTQKMSEKdtke 104
Cdd:cd16196   1 RLRRLFD--KIAGEdMEIDAYELQdilntAFKKDFPFDGfSLDACRSMVAMMDVDRSGKLGFEEFKKLWEDLRSWK---- 74

                        90       100       110
                ....*....|....*....|....*....|
gi 4757902  105 eilKAFKLFDDDETGKISFKNLKRVAKELG 134
Cdd:cd16196  75 ---RVFKLFDTDGSGSFSSFELRNALNSAG 101

EF-hand domain;

                          10        20        30
                  ....*....|....*....|....*....|
gi 4757902    105 EILKAFKLFDDDETGKISFKNLKRVAKELG 134
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSLG 30