metallophosphatase superfamily, metallophosphatase domain; Metallophosphatases (MPPs), also known as metallophosphoesterases, phosphodiesterases (PDEs), binuclear metallophosphoesterases, and dimetal-containing phosphoesterases (DMPs), represent a diverse superfamily of enzymes with a conserved domain containing an active site consisting of two metal ions (usually manganese, iron, or zinc) coordinated with octahedral geometry by a cage of histidine, aspartate, and asparagine residues. This superfamily includes: the phosphoprotein phosphatases (PPPs), Mre11/SbcD-like exonucleases, Dbr1-like RNA lariat debranching enzymes, YfcE-like phosphodiesterases, purple acid phosphatases (PAPs), YbbF-like UDP-2,3-diacylglucosamine hydrolases, and acid sphingomyelinases (ASMases). The conserved domain is a double beta-sheet sandwich with a di-metal active site made up of residues located at the C-terminal side of the sheets. This domain is thought to allow for productive metal coordination.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907161138  12 RYGFTKEVMHKYKIHGKKILRTLQDVFCWLPLATLVDEKVLVLHGGVSDKTDLELLAKLDRHKIVSTmrcktrkesenre 91
Cdd:cd07420   128 RYGFTKEVMQKYKDHGKKILRLLEDVFSWLPLATIIDNKVLVVHGGISDSTDLDLLDKIDRHKYVST------------- 194

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907161138  92 eqkrkdnqtssgqkptpwflpqsrslpsspfhlgsgfkaykagrscsipcgspnskelsrrgqvrrsvdleleqcrqqag 171
Cdd:cd07420       --------------------------------------------------------------------------------

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907161138 172 flgirekgeslplapdadcvadgggvleptPEEWKQVVDILWSDPAAQEGCKANAVRGGGCYFGPDVTERLMEKYKLQLL 251
Cdd:cd07420   195 ------------------------------KTEWQQVVDILWSDPKATKGCKPNTFRGGGCYFGPDVTSQFLQKHGLSLL 244

                         250       260       270       280       290
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1907161138 252 IRSHECKPEGYEFCHNRKVLTIFSASNYYEVGSNRGAYVKLGPALTPHIVQYQ 304
Cdd:cd07420   245 IRSHECKPEGYEFCHNNKVITIFSASNYYEEGSNRGAYVKLGPQLTPHFVQYQ 297

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907161138 344 FRKRDPDESGVITLSDWATAVESVlhlglpWRMLRpqlvnssadnvleyrSWLDSLAKEQLSRE---NIQSSLLEKLYRN 420
Cdd:COG5126    11 FDLLDADGDGVLERDDFEALFRRL------WATLF---------------SEADTDGDGRISREefvAGMESLFEATVEP 69

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1907161138 421 RsnLETIFRIIDSDHSGFISLDEFRQTWKlfsshmSIDITDDGICDLARSIDFNKDGHIDINEFLEAFR 489
Cdd:COG5126    70 F--ARAAFDLLDTDGDGKISADEFRRLLT------ALGVSEEEADELFARLDTDGDGKISFEEFVAAVR 130

Drosophila melanogaster RdgC and related proteins, metallophosphatase domain; RdgC (retinal degeneration C) is a vertebrate serine-threonine protein phosphatase that is required to prevent light-induced retinal degeneration. In addition to its catalytic domain, RdgC has two C-terminal EF hands. Homologs of RdgC include the human phosphatases protein phosphatase with EF hands 1 and -2 (PPEF-1 and -2). PPEF-1 transcripts are present at low levels in the retina, PPEF-2 transcripts and PPEF-2 protein are present at high levels in photoreceptors. The PPP (phosphoprotein phosphatase) family, to which RdgC belongs, is one of two known protein phosphatase families specific for serine and threonine. The PPP family also includes: PP1, PP2A, PP2B (calcineurin), PP4, PP5, PP6, PP7, Bsu1, PrpE, PrpA/PrpB, and ApA4 hydrolase. The PPP catalytic domain is defined by three conserved motifs (-GDXHG-, -GDXVDRG- and -GNHE-). The PPP enzyme family is ancient with members found in all eukaryotes, and in most bacterial and archeal genomes. Dephosphorylation of phosphoserines and phosphothreonines on target proteins plays a central role in the regulation of many cellular processes. PPPs belong to the metallophosphatase (MPP) superfamily. MPPs are functionally diverse, but all share a conserved domain with an active site consisting of two metal ions (usually manganese, iron, or zinc) coordinated with octahedral geometry by a cage of histidine, aspartate, and asparagine residues. The MPP superfamily includes: Mre11/SbcD-like exonucleases, Dbr1-like RNA lariat debranching enzymes, YfcE-like phosphodiesterases, purple acid phosphatases (PAPs), YbbF-like UDP-2,3-diacylglucosamine hydrolases, and acid sphingomyelinases (ASMases). The conserved domain is a double beta-sheet sandwich with a di-metal active site made up of residues located at the C-terminal side of the sheets. This domain is thought to allow for productive metal coordination.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907161138  12 RYGFTKEVMHKYKIHGKKILRTLQDVFCWLPLATLVDEKVLVLHGGVSDKTDLELLAKLDRHKIVSTmrcktrkesenre 91
Cdd:cd07420   128 RYGFTKEVMQKYKDHGKKILRLLEDVFSWLPLATIIDNKVLVVHGGISDSTDLDLLDKIDRHKYVST------------- 194

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907161138  92 eqkrkdnqtssgqkptpwflpqsrslpsspfhlgsgfkaykagrscsipcgspnskelsrrgqvrrsvdleleqcrqqag 171
Cdd:cd07420       --------------------------------------------------------------------------------

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907161138 172 flgirekgeslplapdadcvadgggvleptPEEWKQVVDILWSDPAAQEGCKANAVRGGGCYFGPDVTERLMEKYKLQLL 251
Cdd:cd07420   195 ------------------------------KTEWQQVVDILWSDPKATKGCKPNTFRGGGCYFGPDVTSQFLQKHGLSLL 244

                         250       260       270       280       290
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1907161138 252 IRSHECKPEGYEFCHNRKVLTIFSASNYYEVGSNRGAYVKLGPALTPHIVQYQ 304
Cdd:cd07420   245 IRSHECKPEGYEFCHNNKVITIFSASNYYEEGSNRGAYVKLGPQLTPHFVQYQ 297

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 1907161138 424 LETIFRIIDSDHSGFISLDEFRQTWKLFSSHMSIDITDDGIcdlaRSIDFNKDGHIDINEFLEAFR 489
Cdd:cd00051     2 LREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMI----REVDKDGDGKIDFEEFLELMA 63

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907161138 344 FRKRDPDESGVITLSDWATAVESVlhlglpWRMLRpqlvnssadnvleyrSWLDSLAKEQLSRE---NIQSSLLEKLYRN 420
Cdd:COG5126    11 FDLLDADGDGVLERDDFEALFRRL------WATLF---------------SEADTDGDGRISREefvAGMESLFEATVEP 69

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1907161138 421 RsnLETIFRIIDSDHSGFISLDEFRQTWKlfsshmSIDITDDGICDLARSIDFNKDGHIDINEFLEAFR 489
Cdd:COG5126    70 F--ARAAFDLLDTDGDGKISADEFRRLLT------ALGVSEEEADELFARLDTDGDGKISFEEFVAAVR 130

calmodulin; Provisional

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1907161138 424 LETIFRIIDSDHSGFISLDEFRQTWklfsSHMSIDITDDGICDLARSIDFNKDGHIDINEF 484
Cdd:PTZ00184   86 IKEAFKVFDRDGNGFISAAELRHVM----TNLGEKLTDEEVDEMIREADVDGDGQINYEEF 142

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 1907161138  427 IFRIIDSDHSGFISLDEFRQ 446
Cdd:smart00054   5 AFRLFDKDGDGKIDFEEFKD 24

Drosophila melanogaster RdgC and related proteins, metallophosphatase domain; RdgC (retinal degeneration C) is a vertebrate serine-threonine protein phosphatase that is required to prevent light-induced retinal degeneration. In addition to its catalytic domain, RdgC has two C-terminal EF hands. Homologs of RdgC include the human phosphatases protein phosphatase with EF hands 1 and -2 (PPEF-1 and -2). PPEF-1 transcripts are present at low levels in the retina, PPEF-2 transcripts and PPEF-2 protein are present at high levels in photoreceptors. The PPP (phosphoprotein phosphatase) family, to which RdgC belongs, is one of two known protein phosphatase families specific for serine and threonine. The PPP family also includes: PP1, PP2A, PP2B (calcineurin), PP4, PP5, PP6, PP7, Bsu1, PrpE, PrpA/PrpB, and ApA4 hydrolase. The PPP catalytic domain is defined by three conserved motifs (-GDXHG-, -GDXVDRG- and -GNHE-). The PPP enzyme family is ancient with members found in all eukaryotes, and in most bacterial and archeal genomes. Dephosphorylation of phosphoserines and phosphothreonines on target proteins plays a central role in the regulation of many cellular processes. PPPs belong to the metallophosphatase (MPP) superfamily. MPPs are functionally diverse, but all share a conserved domain with an active site consisting of two metal ions (usually manganese, iron, or zinc) coordinated with octahedral geometry by a cage of histidine, aspartate, and asparagine residues. The MPP superfamily includes: Mre11/SbcD-like exonucleases, Dbr1-like RNA lariat debranching enzymes, YfcE-like phosphodiesterases, purple acid phosphatases (PAPs), YbbF-like UDP-2,3-diacylglucosamine hydrolases, and acid sphingomyelinases (ASMases). The conserved domain is a double beta-sheet sandwich with a di-metal active site made up of residues located at the C-terminal side of the sheets. This domain is thought to allow for productive metal coordination.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907161138  12 RYGFTKEVMHKYKIHGKKILRTLQDVFCWLPLATLVDEKVLVLHGGVSDKTDLELLAKLDRHKIVSTmrcktrkesenre 91
Cdd:cd07420   128 RYGFTKEVMQKYKDHGKKILRLLEDVFSWLPLATIIDNKVLVVHGGISDSTDLDLLDKIDRHKYVST------------- 194

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907161138  92 eqkrkdnqtssgqkptpwflpqsrslpsspfhlgsgfkaykagrscsipcgspnskelsrrgqvrrsvdleleqcrqqag 171
Cdd:cd07420       --------------------------------------------------------------------------------

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907161138 172 flgirekgeslplapdadcvadgggvleptPEEWKQVVDILWSDPAAQEGCKANAVRGGGCYFGPDVTERLMEKYKLQLL 251
Cdd:cd07420   195 ------------------------------KTEWQQVVDILWSDPKATKGCKPNTFRGGGCYFGPDVTSQFLQKHGLSLL 244

                         250       260       270       280       290
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1907161138 252 IRSHECKPEGYEFCHNRKVLTIFSASNYYEVGSNRGAYVKLGPALTPHIVQYQ 304
Cdd:cd07420   245 IRSHECKPEGYEFCHNNKVITIFSASNYYEEGSNRGAYVKLGPQLTPHFVQYQ 297

PP5, C-terminal metallophosphatase domain; Serine/threonine protein phosphatase-5 (PP5) is a member of the PPP gene family of protein phosphatases that is highly conserved among eukaryotes and widely expressed in mammalian tissues. PP5 has a C-terminal phosphatase domain and an extended N-terminal TPR (tetratricopeptide repeat) domain containing three TPR motifs. The PPP (phosphoprotein phosphatase) family, to which PP5 belongs, is one of two known protein phosphatase families specific for serine and threonine. The PPP family also includes: PP1, PP2A, PP2B (calcineurin), PP4, PP6, PP7, Bsu1, RdgC, PrpE, PrpA/PrpB, and ApA4 hydrolase. The PPP catalytic domain is defined by three conserved motifs (-GDXHG-, -GDXVDRG- and -GNHE-). The PPP enzyme family is ancient with members found in all eukaryotes, and in most bacterial and archeal genomes. Dephosphorylation of phosphoserines and phosphothreonines on target proteins plays a central role in the regulation of many cellular processes. PPPs belong to the metallophosphatase (MPP) superfamily. MPPs are functionally diverse, but all share a conserved domain with an active site consisting of two metal ions (usually manganese, iron, or zinc) coordinated with octahedral geometry by a cage of histidine, aspartate, and asparagine residues. The MPP superfamily includes: Mre11/SbcD-like exonucleases, Dbr1-like RNA lariat debranching enzymes, YfcE-like phosphodiesterases, purple acid phosphatases (PAPs), YbbF-like UDP-2,3-diacylglucosamine hydrolases, and acid sphingomyelinases (ASMases). The conserved domain is a double beta-sheet sandwich with a di-metal active site made up of residues located at the C-terminal side of the sheets. This domain is thought to allow for productive metal coordination.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907161138  13 YGFTKEVMHKYkihGKKILRTLQDVFCWLPLATLVDEKVLVLHGGV--SDKTDLELLAKLDRHkivstmrcktrkesenr 90
Cdd:cd07417   138 YGFEGEVKAKY---NEQMFNLFSEVFNWLPLAHLINGKVLVVHGGLfsDDGVTLDDIRKIDRF----------------- 197

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907161138  91 eeqkrkdnqtssgqkptpwflpqsrslpsspfhlgsgfkaykagrscsipcgspnskelsrrgqvrrsvdleleqcrqqa 170
Cdd:cd07417       --------------------------------------------------------------------------------

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907161138 171 gflgiREKGESLPLapdadCvadgggvleptpeewkqvvDILWSDPAAQEGcKANAVRGGGCYFGPDVTERLMEKYKLQL 250
Cdd:cd07417   198 -----RQPPDSGLM-----C-------------------ELLWSDPQPQPG-RGPSKRGVGCQFGPDVTKRFLEENNLDY 247

                         250       260       270       280       290
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1907161138 251 LIRSHECKPEGYEFCHNRKVLTIFSASNYYEVGSNRGAYVKL-GPALTPHIVQYQA 305
Cdd:cd07417   248 IIRSHEVKDEGYEVEHDGKCITVFSAPNYCDQMGNKGAFIRFkGSDLKPKFTQFEA 303

PP7, metallophosphatase domain; PP7 is a plant phosphoprotein phosphatase that is highly expressed in a subset of stomata and thought to play an important role in sensory signaling. PP7 acts as a positive regulator of signaling downstream of cryptochrome blue light photoreceptors. PP7 also controls amplification of phytochrome signaling, and interacts with nucleotidediphosphate kinase 2 (NDPK2), a positive regulator of phytochrome signalling. In addition, PP7 interacts with heat shock transcription factor HSF and up-regulates protective heat shock proteins. PP7 may also play a role in salicylic acid-dependent defense signaling. The PPP (phosphoprotein phosphatase) family, to which PP7 belongs, is one of two known protein phosphatase families specific for serine and threonine. The PPP family also includes: PP2A, PP2B (calcineurin), PP4, PP5, PP6, Bsu1, RdgC, PrpE, PrpA/PrpB, and ApA4 hydrolase. The PPP catalytic domain is defined by three conserved motifs (-GDXHG-, -GDXVDRG- and -GNHE-). The PPP enzyme family is ancient with members found in all eukaryotes, and in most bacterial and archeal genomes. Dephosphorylation of phosphoserines and phosphothreonines on target proteins plays a central role in the regulation of many cellular processes. PPPs belong to the metallophosphatase (MPP) superfamily. MPPs are functionally diverse, but all share a conserved domain with an active site consisting of two metal ions (usually manganese, iron, or zinc) coordinated with octahedral geometry by a cage of histidine, aspartate, and asparagine residues. The MPP superfamily includes: Mre11/SbcD-like exonucleases, Dbr1-like RNA lariat debranching enzymes, YfcE-like phosphodiesterases, purple acid phosphatases (PAPs), YbbF-like UDP-2,3-diacylglucosamine hydrolases, and acid sphingomyelinases (ASMases). The conserved domain is a double beta-sheet sandwich with a di-metal active site made up of residues located at the C-terminal side of the sheets. This domain is thought to allow for productive metal coordination.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907161138  11 SRYGFTKEVMHKYKIHGKKILRTLQDVFCWLPLATLVDEKVLVLHGGVSDKTDLELlakldrhkivstmrcktrkesenR 90
Cdd:cd07418   142 SMYGFEQEVLTKYGDKGKHVYRKCLGCFEGLPLASIIAGRVYTAHGGLFRSPSLPK-----------------------R 198

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907161138  91 EEQKRKDNQTSSGQkptpwflPQSRSLPsspfhLGSgfkaykagrscsipcgspnSKELSrrgQVRRSVdleleqcrqqa 170
Cdd:cd07418   199 KKQKGKNRRVLLLE-------PESESLK-----LGT-------------------LDDLM---KARRSV----------- 233

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907161138 171 gflgIREKGESLPLAPDadcvadgggvleptpeewkqvvDILWSDPAAQEGCKANAVRGGGCYFGPDVTERLMEKYKLQL 250
Cdd:cd07418   234 ----LDPPGEGSNLIPG----------------------DVLWSDPSLTPGLSPNKQRGIGLLWGPDCTEEFLEKNNLKL 287

                         250       260       270       280       290       300
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1907161138 251 LIRSHEC------KPE------GYEFCHN---RKVLTIFSASNY------YEVGSNRGAYVKLGP 294
Cdd:cd07418   288 IIRSHEGpdarekRPGlagmnkGYTVDHDvesGKLITLFSAPDYpqfqatEERYNNKGAYIILQP 352

PP1, PPKL (PP1 and kelch-like) enzymes, and related proteins, metallophosphatase domain; PP1 (protein phosphatase type 1) is a serine/threonine phosphatase that regulates many cellular processes including: cell-cycle progression, protein synthesis, muscle contraction, carbohydrate metabolism, transcription and neuronal signaling, through its interaction with at least 180 known targeting proteins. PP1 occurs in all tissues and regulates many pathways, ranging from cell-cycle progression to carbohydrate metabolism. Also included here are the PPKL (PP1 and kelch-like) enzymes including the PPQ, PPZ1, and PPZ2 fungal phosphatases. These PPKLs have a large N-terminal kelch repeat in addition to a C-terminal phosphoesterase domain. The PPP (phosphoprotein phosphatase) family, to which PP1 belongs, is one of two known protein phosphatase families specific for serine and threonine. The PPP family also includes: PP2A, PP2B (calcineurin), PP4, PP5, PP6, PP7, Bsu1, RdgC, PrpE, PrpA/PrpB, and ApA4 hydrolase. The PPP catalytic domain is defined by three conserved motifs (-GDXHG-, -GDXVDRG- and -GNHE-). The PPP enzyme family is ancient with members found in all eukaryotes, and in most bacterial and archeal genomes. Dephosphorylation of phosphoserines and phosphothreonines on target proteins plays a central role in the regulation of many cellular processes. PPPs belong to the metallophosphatase (MPP) superfamily. MPPs are functionally diverse, but all share a conserved domain with an active site consisting of two metal ions (usually manganese, iron, or zinc) coordinated with octahedral geometry by a cage of histidine, aspartate, and asparagine residues. The MPP superfamily includes: Mre11/SbcD-like exonucleases, Dbr1-like RNA lariat debranching enzymes, YfcE-like phosphodiesterases, purple acid phosphatases (PAPs), YbbF-like UDP-2,3-diacylglucosamine hydrolases, and acid sphingomyelinases (ASMases). The conserved domain is a double beta-sheet sandwich with a di-metal active site made up of residues located at the C-terminal side of the sheets. This domain is thought to allow for productive metal coordination.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907161138   4 HVCfASVSR-YGFTKEVMHKYKIhgkKILRTLQDVFCWLPLATLVDEKVLVLHGGVSdktdlellakldrhkivstmrck 82
Cdd:cd07414   118 HEC-ASINRiYGFYDECKRRYNI---KLWKTFTDCFNCLPVAAIVDEKIFCCHGGLS----------------------- 170

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907161138  83 trkesenreeqkrkdnqtssgqkptpwflpqsrslpsspfhlgsgfkaykagrscsipcgspnsKELSRRGQVRRsvdle 162
Cdd:cd07414   171 ----------------------------------------------------------------PDLQSMEQIRR----- 181

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907161138 163 leqcrqqagflgirekgeslplapdadcvadgggVLEPT--PEEwKQVVDILWSDPAAQEGCKANAVRGGGCYFGPDVTE 240
Cdd:cd07414   182 ----------------------------------IMRPTdvPDQ-GLLCDLLWSDPDKDVQGWGENDRGVSFTFGADVVA 226

                         250       260       270       280
                  ....*....|....*....|....*....|....*....|....*...
gi 1907161138 241 RLMEKYKLQLLIRSHECKPEGYEFCHNRKVLTIFSASNYYEVGSNRGA 288
Cdd:cd07414   227 KFLHKHDLDLICRAHQVVEDGYEFFAKRQLVTLFSAPNYCGEFDNAGA 274

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 1907161138 424 LETIFRIIDSDHSGFISLDEFRQTWKLFSSHMSIDITDDGIcdlaRSIDFNKDGHIDINEFLEAFR 489
Cdd:cd00051     2 LREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMI----REVDKDGDGKIDFEEFLELMA 63

PP2B, metallophosphatase domain; PP2B (calcineurin) is a unique serine/threonine protein phosphatase in its regulation by a second messenger (calcium and calmodulin). PP2B is involved in many biological processes including immune responses, the second messenger cAMP pathway, sodium/potassium ion transport in the nephron, cell cycle progression in lower eukaryotes, cardiac hypertrophy, and memory formation. PP2B is highly conserved from yeast to humans, but is absent from plants. PP2B is a heterodimer consisting of a catalytic subunit (CnA) and a regulatory subunit (CnB); CnB contains four Ca2+ binding motifs referred to as EF hands. The PPP (phosphoprotein phosphatase) family, to which PP2B belongs, is one of two known protein phosphatase families specific for serine and threonine. The PPP family also includes: PP1, PP2A, PP4, PP5, PP6, PP7, Bsu1, RdgC, PrpE, PrpA/PrpB, and ApA4 hydrolase. The PPP catalytic domain is defined by three conserved motifs (-GDXHG-, -GDXVDRG- and -GNHE-). The PPP enzyme family is ancient with members found in all eukaryotes, and in most bacterial and archeal genomes. Dephosphorylation of phosphoserines and phosphothreonines on target proteins plays a central role in the regulation of many cellular processes. PPPs belong to the metallophosphatase (MPP) superfamily. MPPs are functionally diverse, but all share a conserved domain with an active site consisting of two metal ions (usually manganese, iron, or zinc) coordinated with octahedral geometry by a cage of histidine, aspartate, and asparagine residues. The MPP superfamily includes: Mre11/SbcD-like exonucleases, Dbr1-like RNA lariat debranching enzymes, YfcE-like phosphodiesterases, purple acid phosphatases (PAPs), YbbF-like UDP-2,3-diacylglucosamine hydrolases, and acid sphingomyelinases (ASMases). The conserved domain is a double beta-sheet sandwich with a di-metal active site made up of residues located at the C-terminal side of the sheets. This domain is thought to allow for productive metal coordination.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907161138 210 DILWSDPAAQEGCKA-------NAVRGGGCYFGPDVTERLMEKYKLQLLIRSHECKPEGYEFCHNRK------VLTIFSA 276
Cdd:cd07416   189 DLLWSDPLEDFGNEKtqehfvhNTVRGCSYFYSYRAVCEFLQKNNLLSIIRAHEAQDAGYRMYRKSQttgfpsLITIFSA 268

                          90
                  ....*....|....*.
gi 1907161138 277 SNYYEVGSNRGAYVKL 292
Cdd:cd07416   269 PNYLDVYNNKAAVLKY 284

serine/threonine-protein phosphatase; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907161138 210 DILWSDPAAQEGCKANAVRGGGCYFGPDVTERLMEKYKLQLLIRSHECKPEGYEFCHNRKVLTIFSASNYYEVGSNRGAY 289
Cdd:PTZ00480  205 DLLWSDPDKDVQGWADNERGVSYVFSQEIVQVFLKKHELDLICRAHQVVEDGYEFFSKRQLVTLFSAPNYCGEFDNAGSM 284

                  ....*..
gi 1907161138 290 VKLGPAL 296
Cdd:PTZ00480  285 MTIDESL 291

serine/threonine protein phosphatase 2A; Provisional

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1907161138 210 DILWSDPAAQEGCKANAvRGGGCYFGPDVTERLMEKYKLQLLIRSHECKPEGYEFCHNRKVL-TIFSASNY-YEVGS 284
Cdd:PTZ00239  190 DLMWSDPEEVEYWAVNS-RGAGYLFGAKVTKEFCRLNDLTLICRAHQLVMEGYKYWFPDQNLvTVWSAPNYcYRCGN 265

EF-hand domain pair;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1907161138 435 HSGFISLDEFRQTWKLFSSHmsiDITDDGICDLARSIDFNKDGHIDINEFLEAF 488
Cdd:pfam13833   1 EKGVITREELKRALALLGLK---DLSEDEVDILFREFDTDGDGYISFDEFCVLL 51

calmodulin; Provisional

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1907161138 424 LETIFRIIDSDHSGFISLDEFRQTWklfsSHMSIDITDDGICDLARSIDFNKDGHIDINEF 484
Cdd:PTZ00184   86 IKEAFKVFDRDGNGFISAAELRHVM----TNLGEKLTDEEVDEMIREADVDGDGQINYEEF 142

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        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1907161138 422 SNLETIFRIIDSDHSGFISLDEFRQTWKLFSSHmSIDITDDGICDLARSIDFNKDGHIDINEF 484
Cdd:cd16251    34 DQIKKVFQILDKDKSGFIEEEELKYILKGFSIA-GRDLTDEETKALLAAGDTDGDGKIGVEEF 95

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 1907161138 387 DNVLEYRSwldsLAKEQLSRENiqsSLLEKLYRNRSNLE----TIFRIIDSDHSGFISLDEFRQTWK-LFS---SHMSID 458
Cdd:cd15902    58 DGKIEIRE----LANILPTEEN---FLLLFRREQPLISSvefmKIWRKYDTDGSGFIEAKELKGFLKdLLLknkKHVSPP 130

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 1907161138 459 ITDDGICDLARSIDFNKDGHIDINEFL------EAFRLVEQ 493
Cdd:cd15902   131 KLDEYTKLILKEFDANKDGKLELDEMAkllpvqENFLLKFQ 171

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 1907161138 423 NLETIFRIIDSDHSGFISLDEFRQ-----TWKLFsshmsiditDDGICDLARSI-DFNKDGHIDINEFLEAFRLVEQscl 496
Cdd:cd16183     1 FLWNVFQRVDKDRSGQISATELQQalsngTWTPF---------NPETVRLMIGMfDRDNSGTINFQEFAALWKYITD--- 68

                          90
                  ....*....|....*..
gi 1907161138 497 eghASACLQSTDTAESG 513
Cdd:cd16183    69 ---WQNCFRSFDRDNSG 82

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 1907161138 428 FRIIDSDHSGFISLDEFRQT-----WKLFSshmsiDITddgiCDLARSI-DFNKDGHIDINEFLEAFRLVEQ 493
Cdd:cd16184     6 FQAVDRDRSGKISAKELQQAlvngnWSHFN-----DET----CRLMIGMfDKDKSGTIDIYEFQALWNYIQQ 68

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
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1907161138 427 IFRIIDSDHSGFISLDEFRQTWKLFSSHMSiDITDDGICDLARSIDFNKDGHIDINEF 484
Cdd:cd16255    39 VFEIIDQDKSGFIEEEELKLFLQNFSSGAR-ELTDAETKAFLKAGDSDGDGKIGVEEF 95

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1907161138 424 LETIFRIIDSDHSGFISLDEFRqtwKLFSsHMSIDITDDGICDLARSIDFNKDGHIDINEFLEAFR-LVEQSCLE 497
Cdd:cd15898     2 LRRQWIKADKDGDGKLSLKEIK---KLLK-RLNIRVSEKELKKLFKEVDTNGDGTLTFDEFEELYKsLTERPELE 72

EF-hand, calcium binding motif, found in parvalbumins; 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        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1907161138 423 NLETIFRIIDSDHSGFISLDEFRQTWKLFSSHMSiDITDDGICDLARSIDFNKDGHIDINEF 484
Cdd:cd16253    35 DIKKVFNILDQDKSGFIEEEELKLFLKNFSDGAR-VLSDKETKNFLAAGDSDGDGKIGVDEF 95

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 1907161138  427 IFRIIDSDHSGFISLDEFRQ 446
Cdd:smart00054   5 AFRLFDKDGDGKIDFEEFKD 24