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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 34485978  10 NKDGHINVQELGDVMkqlgknlsHEELKALISKLDTDGDGKISFEEF---FKSIKKYTKEQELQAMFSVLDQNGDGYITV 86
Cdd:COG5126  17 DGDGVLERDDFEALF--------RRLWATLFSEADTDGDGRISREEFvagMESLFEATVEPFARAAFDLLDTDGDGKISA 88

                        90       100       110       120
                ....*....|....*....|....*....|....*....|..
gi 34485978  87 DELKEGLSKMGepLSQEELEGMIHVFGADQDGKVNYEQFLSH 128
Cdd:COG5126  89 DEFRRLLTALG--VSEEEADELFARLDTDGDGKISFEEFVAA 128

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 34485978   10 NKDGHINVQELGDVMKQLGKNLSHEELKALISKLDTDGDGKISFEEFFKSIKK-------YTKEQELQAMFSVLDQNGDG 82
Cdd:NF041410  39 DGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDELAAAAPPpppppdqAPSTELADDLLSALDTDGDG 118

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 34485978   83 YITVDELKEGLSKMGEPLSQEELegmIHVFGADQDGKVNYEQF 125
Cdd:NF041410 119 SISSDELSAGLTSAGSSADSSQL---FSALDSDGDGSVSSDEL 158

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 34485978    66 EQELQAMFSVLDQNGDGYITVDELKEGLSK--MGEPLSQEELEGMIHVFGADQDGKVNYEQFLSHY 129
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRKleEGEPLSDEEVEELFKEFDLDKDGRISFEEFLELY 66

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 34485978     68 ELQAMFSVLDQNGDGYITVDELKEGLSKM 96
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

centrin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 34485978   10 NKDGHINVQELGDVMKQLGKNLSHEELKALISKLDTDGDGKISFEEFFKSI-----KKYTKEqELQAMFSVLDQNGDGYI 84
Cdd:PTZ00183  29 DGSGTIDPKELKVAMRSLGFEPKKEEIKQMIADVDKDGSGKIDFEEFLDIMtkklgERDPRE-EILKAFRLFDDDKTGKI 107

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 34485978   85 TVDELKEGLSKMGEPLSQEELEGMIHVFGADQDGKVNYEQFLS 127
Cdd:PTZ00183 108 SLKNLKRVAKELGETITDEELQEMIDEADRNGDGEISEEEFYR 150

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 34485978  10 NKDGHINVQELGDVMKQLGKNLSHEELKALISKLDTDGDGKISFEEFFKSIKKY-TKEQELQAMFSVLDQNGDGYITVDE 88
Cdd:COG5126  45 DGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISADEFRRLLTALgVSEEEADELFARLDTDGDGKISFEE 124

                        90
                ....*....|.
gi 34485978  89 LKEGLSKMGEP 99
Cdd:COG5126 125 FVAAVRDYYTP 135

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 34485978   10 NKDGHINVQELGDVMKQLGKNLSHEELKALISKLDTDGDGKISFEEFFKSIKK-------YTKEQELQAMFSVLDQNGDG 82
Cdd:NF041410  39 DGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDELAAAAPPpppppdqAPSTELADDLLSALDTDGDG 118

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 34485978   83 YITVDELKEGLSKMGEPLSQEELegmIHVFGADQDGKVNYEQF 125
Cdd:NF041410 119 SISSDELSAGLTSAGSSADSSQL---FSALDSDGDGSVSSDEL 158

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 34485978   8 EENKDGHINVQELGDVMKQLGKNLSHEELKALISKLDTDGDGKISFEEFFKSIKKYTKEQELQAMFSVLDQNGDGYITVD 87
Cdd:cd15898  10 DKDGDGKLSLKEIKKLLKRLNIRVSEKELKKLFKEVDTNGDGTLTFDEFEELYKSLTERPELEPIFKKYAGTNRDYMTLE 89

                        90       100       110       120
                ....*....|....*....|....*....|....*....|..
gi 34485978  88 ELKEGLSK-MGEPLSQEELEGMIH-VFGADQDGKVNYEQFLS 127
Cdd:cd15898  90 EFIRFLREeQGENVSEEECEELIEkYEPERENRQLSFEGFTN 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
                ....*....|....*....|....*....|....*....|....*..
gi 34485978  10 NKDGHINVQELGDVMKQLGKNLSHEELKALISKLDTDGDGKISFEEF 56
Cdd:cd00051  12 DGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEF 58

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 34485978  34 EELKALISKLDTDGDGKISFEEFFKSIkkytkEQELQAMFSVLDQNGDGYITVDELKEGLSKMGEPLSQEELEGMIHVFG 113
Cdd:COG5126   5 RKLDRRFDLLDADGDGVLERDDFEALF-----RRLWATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLD 79

                        90
                ....*....|....*.
gi 34485978 114 ADQDGKVNYEQFLSHY 129
Cdd:COG5126  80 TDGDGKISADEFRRLL 95

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 34485978  10 NKDGHINVQELGDVMKQ-LGKNLSHEELKALISKLDTDGDGKISFEEF---FKSIKKYtkeqelQAMFSVLDQNGDGYIT 85
Cdd:cd16180  12 DRSGRISAKELQRALSNgDWTPFSIETVRLMINMFDRDRSGTINFDEFvglWKYIQDW------RRLFRRFDRDRSGSID 85

                        90       100       110       120
                ....*....|....*....|....*....|....*....|.
gi 34485978  86 VDELKEGLSKMGEPLSQEELEGMIHVFGADQDGKVNYEQFL 126
Cdd:cd16180  86 FNELQNALSSFGYRLSPQFVQLLVRKFDRRRRGSISFDDFV 126

EF-hand domain pair;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 34485978    10 NKDGHINVQELGDVMKQL--GKNLSHEELKALISKLDTDGDGKISFEEFFKSIK 61
Cdd:pfam13499  14 DGDGYLDVEELKKLLRKLeeGEPLSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

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 34485978   5 FTKEENKDGHINVQELGDV-----MKQLG-KNLSHEELKALISKLDTDGDGKISFEEFFK---SIKKYtkeqelQAMFSV 75
Cdd:cd16196   6 FDKIAGEDMEIDAYELQDIlntafKKDFPfDGFSLDACRSMVAMMDVDRSGKLGFEEFKKlweDLRSW------KRVFKL 79

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
gi 34485978  76 LDQNGDGYITVDELKEGLSKMGEPLSQEELEGMIHVFGaDQDGKVNYEQFLSHYI 130
Cdd:cd16196  80 FDTDGSGSFSSFELRNALNSAGFRLSNATLNALVLRYS-NKDGRISFDDFIMCAV 133

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 34485978  10 NKDGHINVQELGDVMKQLGKNLSHEELKALISKLDTDGDGKISFEEFFKS---IKKYTKEqelqamFSVLDQNGDGYITV 86
Cdd:cd16180  79 DRSGSIDFNELQNALSSFGYRLSPQFVQLLVRKFDRRRRGSISFDDFVEAcvtLKRLTDA------FRKYDTNRTGYATI 152

                .
gi 34485978  87 D 87
Cdd:cd16180 153 S 153

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 34485978  68 ELQAMFSVLDQNGDGYITVDELKEGLSK-MGEPLSQEELEGMIHVFGADQDGKVNYEQF--LSHYIE 131
Cdd:cd16180   1 ELRRIFQAVDRDRSGRISAKELQRALSNgDWTPFSIETVRLMINMFDRDRSGTINFDEFvgLWKYIQ 67

Penta-EF hand, calcium binding motifs, found in calpain-13 (CAPN13), calpain-14 (CAPN14), and similar proteins; CAPN13, also termed calcium-activated neutral proteinase 13 (CANP 13), a 63.6 kDa calpain large subunit that exhibits a restricted tissue distribution with low levels of expression detected only in human testis and lung. In calpain family, CAPN13 is most closely related to calpain-14 (CAPN14). CAPN14, also termed calcium-activated neutral proteinase 14 (CANP 14), is a 76.7 kDa calpain large subunit that is most highly expressed in the oesophagus. Its expression and calpain activity can be induced by IL-13. Both CAPN13 and CAPN14 contain a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2+-binding penta-EF-hand (PEF) domain.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 34485978  28 GKNLSHEELKALISKLDTDGDGKISFEEF---FKSIKKYtkeqelQAMFSVLDQNGDGYITVDELKEGLSKMGEPLSqee 104
Cdd:cd16195  37 GGGFSLDACRSMVALMDLSVNGRLSLEEFsrlWKKLRKY------KDIFQKADVSKSGFLSLSELRNAIQAAGIRVS--- 107

                        90       100
                ....*....|....*....|....*.
gi 34485978 105 lEGMIHVFG---ADQDGKVNYEQFLS 127
Cdd:cd16195 108 -DDLLNLMAlryGDSSGRISFESFIC 132

calmodulin; Provisional

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 34485978    8 EENKDGHINVQELGDVMKQLGKNLSHEELKALISKLDTDGDGKISFEEFFK 58
Cdd:PTZ00184  94 DRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVK 144

EF-hand motif found in phosphoinositide phospholipase C delta (PI-PLC-delta); PI-PLC-delta isozymes represent a class of metazoan PI-PLCs that are some of the most sensitive to calcium among all PLCs. Their activation is modulated by intracellular calcium ion concentration, phospholipids, polyamines, and other proteins, such as RhoAGAP. Like other PI-PLC isozymes, PI-PLC-delta isozymes contain a core set of domains, including an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core, and a single C-terminal C2 domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. There are three PI-PLC-delta isozymes (1, 3 and 4). PI-PLC-delta1 is relatively well characterized. It is activated by high calcium levels generated by other PI-PLC family members, and therefore functions as a calcium amplifier within the cell. Different PI-PLC-delta isozymes have different tissue distribution and different subcellular locations. PI-PLC-delta1 is mostly a cytoplasmic protein, PI-PLC-delta3 is located in the membrane, and PI-PLC-delta4 is predominantly detected in the cell nucleus. PI-PLC-delta isozymes is evolutionarily conserved even in non-mammalian species, such as yeast, slime molds and plants.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 34485978  10 NKDGHINVQELGDVMKQLGKNLSHEELKALISKLDTDGDGKISFEEFFKSIKKYTKEQELQAMFSVLDQNGDgYITVDEL 89
Cdd:cd16202  12 NGDGKLSFKECKKLLKKLNVKVDKDYAKKLFQEADTSGEDVLDEEEFVQFYNRLTKRPEIEELFKKYSGDDE-ALTVEEL 90

                ....*.
gi 34485978  90 KEGLSK 95
Cdd:cd16202  91 RRFLQE 96

EF-hand, calcium binding motif, found in 45 kDa calcium-binding protein (Cab45); Cab45, also termed stromal cell-derived factor 4 (SDF-4), is a soluble, lumenal Golgi resident low-affinity Ca2+-binding protein that contains six copies of the EF-hand Ca2+-binding motif. It is required for secretory pathway calcium ATPase1 (SPCA1)-dependent Ca2+ import into the trans-Golgi network (TGN) and plays an essential role in Ca2+-dependent secretory cargo sorting at the TGN.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 34485978  37 KALISKLDTDGDGKISFEEFFKSIKKYTKEQELQAMF-----------SVLDQNGDGYITVDELKEGLSKMGEPLSQEEL 105
Cdd:cd16225 171 KEILHDLDQDGDEKLTLDEFVSLPPGTVEEQQAEDDDewkkerkkefeEVIDLNHDGKVTKEELEEYMDPRNERHALNEA 250

                        90       100
                ....*....|....*....|....
gi 34485978 106 EGMIHVFGADQDGKVNYEQFLSHY 129
Cdd:cd16225 251 KQLIAVADENKDGKLSLEEILKNS 274

EF-hand, calcium binding motif, found in reticulocalbin-2 (RCN2) mainly from protostomes; This family corresponds to a group of uncharacterized RCN2-like proteins, which are mainly found in protostomes. Although their biological function remains unclear, they show high sequence similarity with RCN2 (also known as E6BP or TCBP-49), which is an endoplasmic reticulum resident low-affinity Ca2+-binding protein that has been implicated in immunity, redox homeostasis, cell cycle regulation and coagulation. Members in this family contain six copies of the EF-hand Ca2+-binding motif, but may lack a C-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide that is required for retention of RCN2 in the endoplasmic reticulum (ER).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 34485978   9 ENKDGHINVQELGDVMKQLGKNLSHEELKALISKLDTDGDGKISFEEFFKSIKKYTKEQELQA----------------- 71
Cdd:cd16227  47 LNDDGFIDRKELKAWILRSFKMLDEEEANERFEEADEDGDGKVTWEEYLADSFGYDDEDNEEMikdsteddlklleddke 126

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 34485978  72 MFSVLDQNGDGYITVDELKEGLSKMGEP-LSQEELEGMIHVFGADQDGKVNYEQFLS 127
Cdd:cd16227 127 MFEAADLNKDGKLDKTEFSAFQHPEEYPhMHPVLIEQTLRDKDKDNDGFISFQEFLG 183

EF-hand, calcium binding motif, found in 45 kDa calcium-binding protein (Cab45); Cab45, also termed stromal cell-derived factor 4 (SDF-4), is a soluble, lumenal Golgi resident low-affinity Ca2+-binding protein that contains six copies of the EF-hand Ca2+-binding motif. It is required for secretory pathway calcium ATPase1 (SPCA1)-dependent Ca2+ import into the trans-Golgi network (TGN) and plays an essential role in Ca2+-dependent secretory cargo sorting at the TGN.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 34485978  11 KDGHINV---QE--LGDVMKQlGKNLSHEE----LKALISKLDTDGDGKISFEEFFKSIKKYTKE------QELQAMFSV 75
Cdd:cd16225   3 RDGHLNKefhKEvfLGNEKEE-FEEDSEPKkrkkLKEIFKKVDVNTDGFLSAEELEDWIMEKTQEhfqeavEENEQIFKA 81

                        90       100       110
                ....*....|....*....|....*....|....
gi 34485978  76 LDQNGDGYITVDELKEGLSKMGEPlSQEELEGMI 109
Cdd:cd16225  82 VDTDKDGNVSWEEYRVHFLLSKGY-SEEEAEEKI 114

Penta-EF hand, calcium binding motifs, found in sorcin; Sorcin, also termed 22 kDa Ca2+-binding protein, CP-22, or V19, is a soluble resistance-related calcium-binding protein that is expressed in normal mammalian tissues, such as the liver, lungs and heart. The up-regulation of sorcin is correlated with a number of cancer types, including colorectal, gastric and breast cancer. It may represent a therapeutic target for reversing tumor multidrug resistance (MDR). Sorcin participates in the regulation of calcium homeostasis in cells and is necessary for the activation of mitosis and cytokinesis. It enhances metastasis and promotes epithelial-to-mesenchymal transition of colorectal cancer. Moreover, sorcin has been implicated in the regulation of intracellular Ca2+ cycling and cardiac excitation-contraction coupling. It displays the anti-apoptotic properties via the modulation of mitochondrial Ca2+ handling in cardiac myocytes. It can target and activate the sarcolemmal Na+/Ca2+ exchanger (NCX1) in cardiac muscle. Meanwhile, sorcin modulates cardiac L-type Ca2+ current by functional interaction with the alpha1C subunit. It also associates with calcium/calmodulin-dependent protein kinase IIdeltaC (CaMKIIdelta(C)) and further modulates ryanodine receptor (RyR) function in cardiac myocytes. Furthermore, sorcin may act as a Ca2+ sensor for glucose-induced nuclear translocation and the activation of carbohydrate-responsive element-binding protein (ChREBP)-dependent genes. As a mitochondrial chaperone TRAP1 interactor, sorcin involves in mitochondrial metabolism through the TRAP1 pathway. In addition, sorcin may regulate the inhibition of type I interferon response in cells through interacting with foot-and-mouth disease virus (FMDV) VP1. Sorcin contains a flexible glycine and proline-rich N-terminal extension and five EF-hand motifs that associate with membranes in a calcium-dependent manner. It may harbor three potential Ca2+ binding sites through its EF1, EF2 and EF3 hands. However, binding of only two Ca2+/monomer suffices to trigger the conformational change that exposes hydrophobic regions and leads to interaction with the respective targets. Sorcin forms homodimers through the association of the unpaired EF5 hand. Among the PEF proteins, sorcin is unique in that it contains potential phosphorylation sites by cAMP-dependent protein kinase (PKA), and it can form a tetramer at slightly acid pH values although remaining a stable dimer at neutral pH.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 34485978   5 FTKEENKDGHINVQELGDVMKQLG-----KNLSHEELKALISKLDTDGDGKISFEEFfksikkytkeQELQAM------- 72
Cdd:cd16187   6 FAAVAGQDGQIDADELQRCLTQSGiaggyKPFNLETCRLMISMLDRDMSGTMGFNEF----------KELWAVlngwrqh 75

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
gi 34485978  73 FSVLDQNGDGYITVDELKEGLSKMGEPLSQEELEGMIHVFGAdqDGKVNYEQFLS 127
Cdd:cd16187  76 FISFDSDRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRYST--NGKITFDDYIA 128

phosphatidylserine decarboxylase

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 34485978   37 KALISKLDTDGDGKISFEEFFKSIKKY---TKEQELQAMFSVLDQNGDGYITVDELKE--GLSKMGEPL----------- 100
Cdd:PLN02964 182 RRILAIVDYDEDGQLSFSEFSDLIKAFgnlVAANKKEELFKAADLNGDGVVTIDELAAllALQQEQEPIinncpvcgeal 261

                         90
                 ....*....|..
gi 34485978  101 -SQEELEGMIHV 111
Cdd:PLN02964 262 gVSDKLNAMIHM 273

EF-hand, calcium binding motif, found in CREC-EF hand family; The CREC (Cab45/reticulocalbin/ERC45/calumenin)-EF hand family contains a group of six EF-hand, low-affinity Ca2+-binding proteins, including reticulocalbin (RCN-1), ER Ca2+-binding protein of 55 kDa (ERC-55, also known as TCBP-49 or E6BP), reticulocalbin-3 (RCN-3), Ca2+-binding protein of 45 kDa (Cab45 and its splice variant Cab45b), and calumenin ( also known as crocalbin or CBP-50). The proteins are not only localized in various parts of the secretory pathway, but also found in the cytosolic compartment and at the cell surface. They interact with different ligands or proteins and have been implicated in the secretory process, chaperone activity, signal transduction as well as in a large variety of disease processes.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 34485978  36 LKALISKLDTDGDGKISFEEFFKSIKKYTKEQELQAMFSV--------LDQNGDGYITVDELKEGLSKMGEPLSQEELEG 107
Cdd:cd15899 162 IKETLEDLDKNGDGFISLEEFISDPYSADENEEEPEWVKVekerfvelRDKDKDGKLDGEELLSWVDPSNQEIALEEAKH 241

                        90       100
                ....*....|....*....|..
gi 34485978 108 MIHVFGADQDGKVNYEQFLSHY 129
Cdd:cd15899 242 LIAESDENKDGKLSPEEILDNH 263

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 34485978   8 EENKDGHINVQELGDVMKQL---GKNLSHEELKALISKLDTDGDGKISFEEFFKSIK 61
Cdd:cd16251  44 DKDKSGFIEEEELKYILKGFsiaGRDLTDEETKALLAAGDTDGDGKIGVEEFATLVA 100

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 34485978  10 NKDGHINVQELGDVMKQLGKNLSHEELKALISKLDTDGDGKISFEEFfksIKKYTKEQELQAMFSVLDQNGDGYITV 86
Cdd:cd16184  79 DRSGSIDENELHQALSQMGYRLSPQFVQFLVSKYDPRARRSLTLDQF---IQVCVQLQSLTDAFRQRDTQMTGTITI 152

calmodulin; Provisional

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 34485978   67 QELQAMFSVLDQNGDGYITVDELKEGLSKMGEPLSQEELEGMIHVFGADQDGKVNYEQFLS 127
Cdd:PTZ00184  11 AEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLT 71

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 34485978   5 FTKEENKDGHINVQELGDVMKQL--------GKNLSHEELKALISKLDTDGDGKISFEEFFksiKKYTKEQELQAMFSVL 76
Cdd:cd16199   6 FAQLAGEDAEISAFELQTILRRVlakredikSDGFSIETCKIMVDMLDSDGSGKLGLKEFY---ILWTKIQKYQKIYREI 82

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 34485978  77 DQNGDGYITVDELKEGLSKMGEPLSQEELEGMIHVFgADQDGKVNYEQFLSHYI--ETVYKV 136
Cdd:cd16199  83 DVDRSGTMNSYEMRKALEEAGFKLPCQLHQVIVARF-ADDDLIIDFDNFVRCLVrlETLFKI 143

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

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 34485978  64 TKEQELQAMFSVLDQNGDGYITVDELKEGLSKMgeplsqeeLEGMIHVFGADQDGKVNYEQFLSHY 129
Cdd:COG5126   2 LQRRKLDRRFDLLDADGDGVLERDDFEALFRRL--------WATLFSEADTDGDGRISREEFVAGM 59

N-terminal domain of Myosin essential light chain ELC; ELC is part of the apicomplexan membrane-associated protein complex called the glideosome, which is essential for parasite motility. The glideosome is composed of six proteins: myosin A (MyoA), essential light chain ELC, myosin light chain MLC1 (also called MTIP), and the glideosome-associated proteins GAP40, GAP45, and GAP50. MyoA is a Class XIV myosin implicated in gliding motility, as well as host cell and tissue invasion by parasites. ELC binds to the MyoA neck region adjacent to the MLC1-binding site, and both myosin light chains co-located to the glideosome. Although ELCs bind to a conserved MyoA sequence, P. falciparum ELC adopts a distinct structure in the free and MyoA-bound state. Therefore ELCs enhance MyoA performance by inducing alpha helical structure formation in MyoA and thus stiffening its lever arm. It has been shown that disruption of MyoA, MLC1, or ELC have dramatic effects on parasite motility but do not affect parasite shape or replication. The ELC N-terminal domain is part of the EF-hand calcium binding motif superfamily. Calcium binding has no effect on the structure of ELCs.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 34485978  66 EQELQAMFSVLDQNGDGYITVDELKEGLSKMGEPLSQEELEGMihvfgadqDGKVNYEQFLS 127
Cdd:cd22949   2 EEKFREAFILFDRDGDGELTMYEAVLAMRSCGIPLTNDEKDAL--------PASMNWDQFEN 55

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 34485978   8 EENKDGHINVQELGDVMKQLGKNLSHEEL---------KALISKLDTDGDGKISFEEF-------------FKSIKKYTK 65
Cdd:cd15902   9 DADGNGYIEGKELDSFLRELLKALNGKDKtddevaekkKEFMEKYDENEDGKIEIRELanilpteenflllFRREQPLIS 88

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 34485978  66 EQELQAMFSVLDQNGDGYITVDELKEGLS--------KMGEPLSQEELEGMIHVFGADQDGKVNYEQF 125
Cdd:cd15902  89 SVEFMKIWRKYDTDGSGFIEAKELKGFLKdlllknkkHVSPPKLDEYTKLILKEFDANKDGKLELDEM 156