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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2062782437 377 GRIGIEEFAEYLklpvSDVLRQLFALFDRNHDGSIDFREYVIGLAVLCNPANTEEIIQvAFKLFDVDEDGFITEEEFSTI 456
Cdd:COG5126    20 GVLERDDFEALF----RRLWATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARA-AFDLLDTDGDGKISADEFRRL 94

                          90       100       110
                  ....*....|....*....|....*....|....
gi 2062782437 457 LQAsLGVPDLDVSGLFKEI-AQGD-SISYGEVQA 488
Cdd:COG5126    95 LTA-LGVSEEEADELFARLdTDGDgKISFEEFVA 127

1-acyl-sn-glycerol-3-phosphate acyltransferase [Lipid transport and metabolism]; 1-acyl-sn-glycerol-3-phosphate acyltransferase is part of the Pathway/BioSystem: Phospholipid biosynthesis

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2062782437 102 WKRKITHPVLKFLGHAMFFSMGFVVTVKGKIATPLEAPIFVVAPHSTFFDGIAcVAAGLP---SIVSRNENVQVPLIGRI 178
Cdd:COG0204     7 LLRRFRYRLVRLWARLLLRLLGVRVRVEGLENLPADGPVLIVANHQSWLDILL-LLAALPrpvRFVAKKELFKIPLLGWL 85

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2062782437 179 LRALQPVLVSRVDPDSRKNTINEIIRRATSGGewpQILVFPEGTCTNRSCLITFKPGAFI----PGVPVQPILLRYpnkl 254
Cdd:COG0204    86 LRALGAIPVDRSKRRAALRALRQAVEALKAGE---SLVIFPEGTRSPDGRLLPFKTGAARlaleAGVPIVPVAIDG---- 158

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2062782437 255 dtvTWTWQGYTFIQLcvltwcqpFTRVEVEFMPVQVPSDEERSDPVLFASTIRNVMAEALK 315
Cdd:COG0204   159 ---TERALPKGFLPR--------PGKVTVRIGPPIDPSDLEGEDRRELAERLRAAIEALLA 208

Acyltransferase; This family contains acyltransferases involved in phospholipid biosynthesis and other proteins of unknown function. This family also includes tafazzin, the Barth syndrome gene.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2062782437 126 VTVKGKIATPLEAPIFVVAPHSTFFDGI--ACVAA---GLPSIVSRNENVQVPLIGRILRALQPVLVSRVDPDSRKNTIn 200
Cdd:pfam01553   2 IEVHGLENLPRGGPAIVVANHQSYLDVLllSLALYkrgRPLVFVAKKELFDIPLVGWLMRLLGCIFIDRKNRKDAAGTL- 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|
gi 2062782437 201 EIIRRATSGGEWpqILVFPEGTCTNRSCLITFKPGAFI----PGVPVQPI 246
Cdd:pfam01553  81 EYLVELLREGKL--VVIFPEGTRSREGELLPFKKGAFRlaieAGVPIVPV 128

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 2062782437 396 LRQLFALFDRNHDGSIDFREYVIGLAVLcNPANTEEIIQVAFKLFDVDEDGFITEEEFSTILQ 458
Cdd:cd00051     2 LREAFRLFDKDGDGTISADELKAALKSL-GEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

1-acyl-sn-glycerol-3-phosphate acyltransferases; This model describes the core homologous region of a collection of related proteins, several of which are known to act as 1-acyl-sn-glycerol-3-phosphate acyltransferases (EC 2.3.1.51). Proteins scoring above the trusted cutoff are likely to have the same general activity. However, there is variation among characterized members as to whether the acyl group can be donated by acyl carrier protein or coenzyme A, and in the length and saturation of the donated acyl group. 1-acyl-sn-glycerol-3-phosphate acyltransferase is also called 1-AGP acyltransferase, lysophosphatidic acid acyltransferase, and LPA acyltransferase. [Fatty acid and phospholipid metabolism, Biosynthesis]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2062782437 123 GFVVTVKGKIATPLEAPIFVVAPHSTFFDGIACVAAGLP--SIVSRNENVQVPLIGRILRALQPVLVSRVDP---DSRKN 197
Cdd:TIGR00530   1 GLKVEVVGPENLPAKSPVLVVANHQSNLDPLTLSAAFPPpiVFIAKKELKWIPFFGIMLWLTGAIFIDRENIraiATALK 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 2062782437 198 TINEIIRRATSggewpqILVFPEGTCTNRSCLITFKPGAFI----PGVPVQPILLR 249
Cdd:TIGR00530  81 AAIEVLKQGRS------IGVFPEGTRSRGRDILPFKKGAFHiaikAGVPILPVVLS 130

glycerol acyltransferase family protein

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2062782437 103 KRKITHPVLKFLGHAMFFSMGFVVTVKGKIATPLEAPIFVvAPHSTFFDGIA-CVAAGLPSIVSRNENVQVPLIGRILRA 181
Cdd:PLN02833  129 RKKIERKLVELICSAFVASWTGVIKYHGPRPSRRPKQVFV-ANHTSMIDFIVlEQMTPFAVIMQKHPGWVGFLQNTILES 207

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2062782437 182 LQPVLVSRVDPDSRkNTINEIIRRATSGGEWPQILVFPEGTCTNRSCLITFKPGAFIPGVPVQPILLRYPNKLDTVTWTW 261
Cdd:PLN02833  208 VGCIWFNRTEAKDR-EVVAKKLRDHVQDPDRNPLLIFPEGTCVNNEYTVMFKKGAFELGCTVCPIAIKYNKIFVDAFWNS 286

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....
gi 2062782437 262 QGYTFIQ-LCVL--TWCqpfTRVEVEFMPVQVPSDEErsDPVLFASTIRNVMAE 312
Cdd:PLN02833  287 RKQSFTMhLLRLmtSWA---VVCDVWYLEPQTLRPGE--TPIEFAERVRDMIAK 335

1-acyl-sn-glycerol-3-phosphate acyltransferase [Lipid transport and metabolism]; 1-acyl-sn-glycerol-3-phosphate acyltransferase is part of the Pathway/BioSystem: Phospholipid biosynthesis

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2062782437 102 WKRKITHPVLKFLGHAMFFSMGFVVTVKGKIATPLEAPIFVVAPHSTFFDGIAcVAAGLP---SIVSRNENVQVPLIGRI 178
Cdd:COG0204     7 LLRRFRYRLVRLWARLLLRLLGVRVRVEGLENLPADGPVLIVANHQSWLDILL-LLAALPrpvRFVAKKELFKIPLLGWL 85

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2062782437 179 LRALQPVLVSRVDPDSRKNTINEIIRRATSGGewpQILVFPEGTCTNRSCLITFKPGAFI----PGVPVQPILLRYpnkl 254
Cdd:COG0204    86 LRALGAIPVDRSKRRAALRALRQAVEALKAGE---SLVIFPEGTRSPDGRLLPFKTGAARlaleAGVPIVPVAIDG---- 158

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2062782437 255 dtvTWTWQGYTFIQLcvltwcqpFTRVEVEFMPVQVPSDEERSDPVLFASTIRNVMAEALK 315
Cdd:COG0204   159 ---TERALPKGFLPR--------PGKVTVRIGPPIDPSDLEGEDRRELAERLRAAIEALLA 208

Lysophospholipid Acyltransferases (LPLATs) of Glycerophospholipid Biosynthesis: AGPAT-like; Lysophospholipid acyltransferase (LPLAT) superfamily member: acyltransferases of de novo and remodeling pathways of glycerophospholipid biosynthesis which catalyze the incorporation of an acyl group from either acylCoAs or acyl-acyl carrier proteins (acylACPs) into acceptors such as glycerol 3-phosphate, dihydroxyacetone phosphate or lyso-phosphatidic acid. Included in this subgroup are such LPLATs as 1-acyl-sn-glycerol-3-phosphate acyltransferase (AGPAT, PlsC), Tafazzin (product of Barth syndrome gene), and similar proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2062782437 116 HAMFFSMGFVVTVKGKIATPLEAPIFVVAPHSTFFDGIACVAAGLPSI--VSRNENVQVPLIGRILRALQPVLVSRVDPD 193
Cdd:cd07989     2 RLLLRLLGVRVRVEGLENLPPKGPVIIVANHQSYLDPLVLGAALPRPIrfVAKKELFKIPFLGWLLRLLGAIPIDRGNGR 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2062782437 194 SRKNTINEIIRRATSGGewpQILVFPEGTCTNRSCLITFKPGAFI----PGVPVQPILLRYPNKLDTVTWTWQGYTFIQL 269
Cdd:cd07989    82 SAREALREAIEALKEGE---SVVIFPEGTRSRDGELLPFKSGAFRlakeAGVPIVPVAISGTWGSLPKGKKLPRPGRVTV 158

                  ...
gi 2062782437 270 CVL 272
Cdd:cd07989   159 RIG 161

Lysophospholipid acyltransferases (LPLATs) of glycerophospholipid biosynthesis; Lysophospholipid acyltransferase (LPLAT) superfamily members are acyltransferases of de novo and remodeling pathways of glycerophospholipid biosynthesis. These proteins catalyze the incorporation of an acyl group from either acylCoAs or acyl-acyl carrier proteins (acylACPs) into acceptors such as glycerol 3-phosphate, dihydroxyacetone phosphate or lyso-phosphatidic acid. Included in this superfamily are LPLATs such as glycerol-3-phosphate 1-acyltransferase (GPAT, PlsB), 1-acyl-sn-glycerol-3-phosphate acyltransferase (AGPAT, PlsC), lysophosphatidylcholine acyltransferase 1 (LPCAT-1), lysophosphatidylethanolamine acyltransferase (LPEAT, also known as, MBOAT2, membrane-bound O-acyltransferase domain-containing protein 2), lipid A biosynthesis lauroyl/myristoyl acyltransferase, 2-acylglycerol O-acyltransferase (MGAT), dihydroxyacetone phosphate acyltransferase (DHAPAT, also known as 1 glycerol-3-phosphate O-acyltransferase 1) and Tafazzin (the protein product of the Barth syndrome (TAZ) gene).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2062782437 120 FSMGFVVTVKGKIATPLEAPIFVVAPHSTFFDG---IACVAAGLPS----IVSRNENVQVPLIGRilraLQPVLVSRVDP 192
Cdd:cd06551     8 FFGFVRLEVKGPPPPPGGGPVLFVSNHSSWWDGlilFLLLERGLRRdvygLMDEELLERYPFFTR----LGAFSVDRDSP 83

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 2062782437 193 DSRKNTINEIIRRATSGGEWpqILVFPEGTCTNRS-CLITFKPGAFIP----GVPVQPILLRYPN 252
Cdd:cd06551    84 RSAAKSLKYVARLLSKPGSV--VWIFPEGTRTRRDkRPLQFKPGVAHLaekaGVPIVPVALRYTF 146

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 2062782437 396 LRQLFALFDRNHDGSIDFREYVIGLAVLcNPANTEEIIQVAFKLFDVDEDGFITEEEFSTILQ 458
Cdd:cd00051     2 LREAFRLFDKDGDGTISADELKAALKSL-GEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

Lysophospholipid Acyltransferases (LPLATs) of Glycerophospholipid Biosynthesis: Unknown AAK14816-like; Lysophospholipid acyltransferase (LPLAT) superfamily member: acyltransferases of de novo and remodeling pathways of glycerophospholipid biosynthesis which catalyze the incorporation of an acyl group from either acylCoAs or acyl-acyl carrier proteins (acylACPs) into acceptors such as glycerol 3-phosphate, dihydroxyacetone phosphate or lyso-phosphatidic acid. Included in this subgroup are uncharacterized glycerol-3-phosphate acyltransferases such as the Plasmodium falciparum locus AAK14816 putative acyltransferase, and similar proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2062782437 126 VTVKGKIATPLEAPIFVVAPHS-TFFDG--IACVAAGLPSIVSRNENVQVPLIGRILRALQPVLVSRVdPDSRKNTINEI 202
Cdd:cd07992    16 ITVVGRENVPKDGPVIFLGNHPnALIDPllLAATLRRPVRFLAKADLFKNPLIGWLLESFGAIPVYRP-KDLARGGIGKI 94

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2062782437 203 IRRAT--------SGGEWpqILVFPEGTCTNRSCLITFKPGAFI----------PGVPVQPILLRYPNK 253
Cdd:cd07992    95 SNAAVfdavgealKAGGA--IGIFPEGGSHDRPRLLPLKAGAARmalealeagqKDVKIVPVGLNYEDK 161

centrin; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2062782437 373 SSKGGRIGIEEFAEYLKL----PVSDVLRQLFALFDRNHDGSIDFREYVIGLAVLCNPANTEEIIQVAFKLFDVDEDGFI 448
Cdd:PTZ00183   28 TDGSGTIDPKELKVAMRSlgfePKKEEIKQMIADVDKDGSGKIDFEEFLDIMTKKLGERDPREEILKAFRLFDDDKTGKI 107

                  .
gi 2062782437 449 T 449
Cdd:PTZ00183  108 S 108

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 2062782437 377 GRIGIEEFAEYLK-LPVSD-VLRQLFALFDRNHDGSIDFREYVIGLAVLCNPA 427
Cdd:COG5126    84 GKISADEFRRLLTaLGVSEeEADELFARLDTDGDGKISFEEFVAAVRDYYTPD 136

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 2062782437 395 VLRQLFALFDRNHDGSIDFREyVIGLAVLCNPANTEEIIQVAFKLFDVDEDGFITEEEFSTILQASLGVPDLDVsgLFKE 474
Cdd:cd15898     1 WLRRQWIKADKDGDGKLSLKE-IKKLLKRLNIRVSEKELKKLFKEVDTNGDGTLTFDEFEELYKSLTERPELEP--IFKK 77

                  ....*
gi 2062782437 475 IAQGD 479
Cdd:cd15898    78 YAGTN 82

1-acyl-sn-glycerol-3-phosphate acyltransferase

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2062782437 102 WKRKITHPVLKF---LGHAMFFSmgfvVTVKGKIATP-LEAPIFVVAPHSTFFDGIACVAAGLP-SIVSRNENVQVPLIG 176
Cdd:PLN02901   14 YRRKAQHFINKVwatLSTSPFYK----IEVEGLENLPsPDEPAVYVSNHQSFLDIYTLFHLGRPfKFISKTSIFLIPIIG 89

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2062782437 177 RILRALQPVLVSRVDPDSRKNTIN---EIIRRATSggewpqILVFPEGTCTNRSCLITFKPGAFI----PGVPVQPILL 248
Cdd:PLN02901   90 WAMYMTGHIPLKRMDRRSQLECLKrcmELLKKGAS------VFFFPEGTRSKDGKLAAFKKGAFSvaakTGVPVVPITL 162

S-100: S-100 domain, which represents the largest family within the superfamily of proteins carrying the Ca-binding EF-hand motif. Note that this S-100 hierarchy contains only S-100 EF-hand domains, other EF-hands have been modeled separately. S100 proteins are expressed exclusively in vertebrates, and are implicated in intracellular and extracellular regulatory activities. Intracellularly, S100 proteins act as Ca-signaling or Ca-buffering proteins. The most unusual characteristic of certain S100 proteins is their occurrence in extracellular space, where they act in a cytokine-like manner through RAGE, the receptor for advanced glycation products. Structural data suggest that many S100 members exist within cells as homo- or heterodimers and even oligomers; oligomerization contributes to their functional diversification. Upon binding calcium, most S100 proteins change conformation to a more open structure exposing a hydrophobic cleft. This hydrophobic surface represents the interaction site of S100 proteins with their target proteins. There is experimental evidence showing that many S100 proteins have multiple binding partners with diverse mode of interaction with different targets. In addition to S100 proteins (such as S100A1,-3,-4,-6,-7,-10,-11,and -13), this group includes the ''fused'' gene family, a group of calcium binding S100-related proteins. The ''fused'' gene family includes multifunctional epidermal differentiation proteins - profilaggrin, trichohyalin, repetin, hornerin, and cornulin; functionally these proteins are associated with keratin intermediate filaments and partially crosslinked to the cell envelope. These ''fused'' gene proteins contain N-terminal sequence with two Ca-binding EF-hands motif, which may be associated with calcium signaling in epidermal cells and autoprocessing in a calcium-dependent manner. In contrast to S100 proteins, "fused" gene family proteins contain an extraordinary high number of almost perfect peptide repeats with regular array of polar and charged residues similar to many known cell envelope proteins.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 2062782437 383 EFAEYLKLPVS-DVLRQLFALFDRNHDGSIDFREY---VIGLAVLCN 425
Cdd:cd00213    39 ELPNFLKNQKDpEAVDKIMKDLDVNKDGKVDFQEFlvlIGKLAVACH 85

EF-hand-like motif found in the dystrophin/dystrobrevin/dystrotelin family; The dystrophin/dystrobrevin/dystrotelin family has been characterized by a compact cluster of domains comprising four EF-hand-like motifs and a ZZ-domain, followed by a looser region with two coiled-coils. Dystrophin is the founder member of this family. It is a sub-membrane cytoskeletal protein associated with the inner surface membrane. Dystrophin and its close paralog utrophin have a large N-terminal extension of actin-binding CH domains, up to 24 spectrin repeats, and a WW domain. Its further paralog, dystrophin-related protein 2 (DRP-2), retains only two of the spectrin repeats. Dystrophin, utrophin or DRP2 can form the core of a membrane-bound complex consisting of dystroglycan, sarcoglycans and syntrophins, known as the dystrophin-glycoprotein complex (DGC) that plays an important role in brain development and disease, as well as in the prevention of muscle damage. Dystrobrevins, including alpha- and beta-dystrobrevin, lack the large N-terminal extension found in dystrophin, but alpha-dystrobrevin has a characteristic C-terminal extension. Dystrobrevins are part of the DGC. They physically associate with members of the dystrophin family and with the syntrophins through their homologous C-terminal coiled coil motifs. In contrast, dystrotelins lack both the large N-terminal extension found in dystrophin and the obvious syntrophin-binding sites (SBSs). Dystrotelins are not critical for mammalian development. They may be involved in other forms of cytokinesis. Moreover, dystrotelin is unable to heterodimerize with members of the dystrophin or dystrobrevin families, or to homodimerize.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2062782437 399 LFALFDRNHDGSIDFREYVIGLAVLCNpANTEEIIQVAFKLFDvDEDGFITEEEFSTILQASLGVPDldvsgLFKEiaqg 478
Cdd:cd15901    59 LLNLYDRNRTGCIRLLSVKIALITLCA-ASLLDKYRYLFGQLA-DSSGFISRERLTQFLQDLLQIPD-----LIGE---- 127

                          90
                  ....*....|....*.
gi 2062782437 479 dSISYGEVQATPSVVS 494
Cdd:cd15901   128 -SPAFGGHNVEAAVES 142

EF-hand domain;

                          10        20
                  ....*....|....*....|....*..
gi 2062782437 433 IQVAFKLFDVDEDGFITEEEFSTILQA 459
Cdd:pfam13405   2 LREAFKLFDKDGDGKISLEELRKALRS 28

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 2062782437 396 LRQLFALFDRNHDGSIDFREYVIGLAVLcNPANTEEIIQVAFKLFDVDEDGFITEEEFSTILQASLGVPDLDvsGLFKEI 475
Cdd:cd16202     2 LKDQFRKADKNGDGKLSFKECKKLLKKL-NVKVDKDYAKKLFQEADTSGEDVLDEEEFVQFYNRLTKRPEIE--ELFKKY 78

                  ....
gi 2062782437 476 AQGD 479
Cdd:cd16202    79 SGDD 82

Eps15 homology domain; found in proteins implicated in endocytosis, vesicle transport, and signal transduction. The alignment contains a pair of EF-hand motifs, typically one of them is canonical and binds to Ca2+, while the other may not bind to Ca2+. A hydrophobic binding pocket is formed by residues from both EF-hand motifs. The EH domain binds to proteins containing NPF (class I), [WF]W or SWG (class II), or H[TS]F (class III) sequence motifs.

                          10        20        30
                  ....*....|....*....|....*....|..
gi 2062782437 389 KLPvSDVLRQLFALFDRNHDGSIDFREYVIGL 420
Cdd:cd00052    29 GLP-RSVLAQIWDLADTDKDGKLDKEEFAIAM 59

EF-hand, calcium binding motif, found in Drosophila melanogaster calbindin-32 (CBN) and similar proteins; CBN, the product of the cbn gene, is a Drosophila homolog to vertebrate neuronal six EF-hand calcium binding proteins. It is expressed through most of ontogenesis with a selective distribution in the nervous system and in a few small adult thoracic muscles. Its precise biological role remains unclear. CBN contains six EF-hand motifs, but some of them may not bind calcium ions due to the lack of key residues.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2062782437 399 LFALFDRNHDGSIDFREYVIGLAV----LCNPAN------TEEIIQVAFKLFDVDEDGFITEEEFSTILQ--ASLGVPDL 466
Cdd:cd16179   146 ILQLFDRNKDGKLQLSEMARLLPVkenfLCRPIFkgagklTREDIDRVFALYDRDNNGTIENEELTGFLKdlLELVQEDY 225

                          90
                  ....*....|.
gi 2062782437 467 DVSGL--FKEI 475
Cdd:cd16179   226 DEQDLeeFKEI 236

EF-hand domain pair;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 2062782437 407 HDGSIDFREYVIGLAVLCNPANTEEIIQVAFKLFDVDEDGFITEEEF 453
Cdd:pfam13833   1 EKGVITREELKRALALLGLKDLSEDEVDILFREFDTDGDGYISFDEF 47

EF hand;

                          10        20
                  ....*....|....*....|....*
gi 2062782437 433 IQVAFKLFDVDEDGFITEEEFSTIL 457
Cdd:pfam13202   1 LKDTFRQIDLNGDGKISKEELRRLL 25

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
                  ....*....|....*....|....*..
gi 2062782437 433 IQVAFKLFDVDEDGFITEEEFSTILQA 459
Cdd:cd15900     2 FEIAFKMFDLDGDGELDKEEFNKVQSI 28

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 2062782437 371 ASSSKGGRIGIEEFAEYLKL---PVSDV-LRQLFALFDRNHDGSIDFREYVIGLAVLCNPantEEIIQVaFKLFDVDEDG 446
Cdd:cd15898     9 ADKDGDGKLSLKEIKKLLKRlniRVSEKeLKKLFKEVDTNGDGTLTFDEFEELYKSLTER---PELEPI-FKKYAGTNRD 84

                          90
                  ....*....|...
gi 2062782437 447 FITEEEFSTILQA 459
Cdd:cd15898    85 YMTLEEFIRFLRE 97

Penta-EF hand, calcium binding motifs, found in mu-type calpain (CAPN1), m-type calpain (CAPN2), and similar proteins; The family includes mu-type calpain (CAPN1) and m-type calpain (CAPN2), both of which are ubiquitously expressed 80-kDa Ca2+-dependent intracellular cysteine proteases that 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 catalytic subunit CAPN1 or CAPN2 in complex with a regulatory subunit encoded by CAPNS1 forms a mu- or m-calpain heterodimer, respectively.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2062782437 324 EDCRLMIS------AGQLtlpmeaGLVEFTKIsrklkldWDGIRKHLDEYAAIASSSKGG------RIGIEEFAEYLKLP 391
Cdd:cd16189    43 ETCRNMVNlldkdgSGKL------GLVEFQIL-------WTKIQKYLKIYKKFDTDGSGTmssyemRLALEEAGFKLNNQ 109

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 2062782437 392 VSDVLRQLFAlfDRNHdgSIDFREYVIGLAVLcnpanteEIIQVAFKLFDVDEDGFI 448
Cdd:cd16189   110 LHQVLVARYA--DQEL--TIDFDNFVRCLVRL-------ELLFKIFKQLDKDNTGTI 155