protein disulfide isomerase, eukaryotic; This model represents eukaryotic protein disulfide isomerases retained in the endoplasmic reticulum (ER) and closely related forms. Some members have been assigned alternative or additional functions such as prolyl 4-hydroxylase and dolichyl-diphosphooligosaccharide-protein glycotransferase. Members of this family have at least two protein-disulfide domains, each similar to thioredoxin but with the redox-active disulfide in the motif PWCGHCK, and an ER retention signal at the extreme C-terminus (KDEL, HDEL, and similar motifs).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617     40 VLTLHADNFDDAIGQHPFILVEFYAPWCGHCKSLAPEYEKAAQLLSKHDPAIVLAKVDANDEKnkPLAGKYEVQGFPTLK 119
Cdd:TIGR01130   3 VLVLTKDNFDDFIKSHEFVLVEFYAPWCGHCKSLAPEYEKAADELKKKGPPIKLAKVDATEEK--DLAQKYGVSGYPTLK 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617    120 IFRNGGKSIQEYKGPREAEGIVEYLKKQVGPASKEIKAPEDAT-YLEDGKIHIVGVFTEFSGPEFTNFLEVAEKLRSYYD 198
Cdd:TIGR01130  81 IFRNGEDSVSDYNGPRDADGIVKYMKKQSGPAVKEIETVADLEaFLADDDVVVIGFFKDLDSELNDTFLSVAEKLRDVYF 160

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617    199 -FGHTVHANHLPRGDAAVERPVVRLFKPFDE---LVVDSKDFDVSALEKFIDASSTPKVVIFDKNPDNHPYLLKFFQSNA 274
Cdd:TIGR01130 161 fFAHSSDVAAFAKLGAFPDSVVLFKPKDEDEkfsKVDGEMDTDVSDLEKFIRAESLPLVGEFTQETAAKYFESGPLVVLY 240

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617    275 pkamLFLNFSTGPFESFKSAYYGAVEEFSGKDVKFLIGDIESSQGAFQYFGLKVDQAPLILIQDGDS-KKFLKEHVEAG- 352
Cdd:TIGR01130 241 ----YNVDESLDPFEELRNRFLEAAKKFRGKFVNFAVADEEDFGRELEYFGLKAEKFPAVAIQDLEGnKKYPMDQEEFSs 316

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617    353 -QIVAWLKDYFDGKLTPFRKSEPIPEANNEPVKVVVADNVHDVVFKSGKNVLIEFYAPWCGHCKKLAPILDEAAATLQS- 430
Cdd:TIGR01130 317 eNLEAFVKDFLDGKLKPYLKSEPIPEDDEGPVKVLVGKNFDEIVLDETKDVLVEFYAPWCGHCKNLAPIYEELAEKYKDa 396

                         410       420       430       440       450       460
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1709617    431 EEDVVIAKMDATENDVPGeFDVQGYPTLYFVTPSGKK--VSYEGGRTADEIVDYIRKNKETAGQ 492
Cdd:TIGR01130 397 ESDVVIAKMDATANDVPP-FEVEGFPTIKFVPAGKKSepVPYDGDRTLEDFSKFIAKHATFPLE 459

protein disulfide isomerase, eukaryotic; This model represents eukaryotic protein disulfide isomerases retained in the endoplasmic reticulum (ER) and closely related forms. Some members have been assigned alternative or additional functions such as prolyl 4-hydroxylase and dolichyl-diphosphooligosaccharide-protein glycotransferase. Members of this family have at least two protein-disulfide domains, each similar to thioredoxin but with the redox-active disulfide in the motif PWCGHCK, and an ER retention signal at the extreme C-terminus (KDEL, HDEL, and similar motifs).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617     40 VLTLHADNFDDAIGQHPFILVEFYAPWCGHCKSLAPEYEKAAQLLSKHDPAIVLAKVDANDEKnkPLAGKYEVQGFPTLK 119
Cdd:TIGR01130   3 VLVLTKDNFDDFIKSHEFVLVEFYAPWCGHCKSLAPEYEKAADELKKKGPPIKLAKVDATEEK--DLAQKYGVSGYPTLK 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617    120 IFRNGGKSIQEYKGPREAEGIVEYLKKQVGPASKEIKAPEDAT-YLEDGKIHIVGVFTEFSGPEFTNFLEVAEKLRSYYD 198
Cdd:TIGR01130  81 IFRNGEDSVSDYNGPRDADGIVKYMKKQSGPAVKEIETVADLEaFLADDDVVVIGFFKDLDSELNDTFLSVAEKLRDVYF 160

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617    199 -FGHTVHANHLPRGDAAVERPVVRLFKPFDE---LVVDSKDFDVSALEKFIDASSTPKVVIFDKNPDNHPYLLKFFQSNA 274
Cdd:TIGR01130 161 fFAHSSDVAAFAKLGAFPDSVVLFKPKDEDEkfsKVDGEMDTDVSDLEKFIRAESLPLVGEFTQETAAKYFESGPLVVLY 240

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617    275 pkamLFLNFSTGPFESFKSAYYGAVEEFSGKDVKFLIGDIESSQGAFQYFGLKVDQAPLILIQDGDS-KKFLKEHVEAG- 352
Cdd:TIGR01130 241 ----YNVDESLDPFEELRNRFLEAAKKFRGKFVNFAVADEEDFGRELEYFGLKAEKFPAVAIQDLEGnKKYPMDQEEFSs 316

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617    353 -QIVAWLKDYFDGKLTPFRKSEPIPEANNEPVKVVVADNVHDVVFKSGKNVLIEFYAPWCGHCKKLAPILDEAAATLQS- 430
Cdd:TIGR01130 317 eNLEAFVKDFLDGKLKPYLKSEPIPEDDEGPVKVLVGKNFDEIVLDETKDVLVEFYAPWCGHCKNLAPIYEELAEKYKDa 396

                         410       420       430       440       450       460
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1709617    431 EEDVVIAKMDATENDVPGeFDVQGYPTLYFVTPSGKK--VSYEGGRTADEIVDYIRKNKETAGQ 492
Cdd:TIGR01130 397 ESDVVIAKMDATANDVPP-FEVEGFPTIKFVPAGKKSepVPYDGDRTLEDFSKFIAKHATFPLE 459

PDIa family, C-terminal TRX domain (a') subfamily; composed of the C-terminal redox active a' domains of PDI, ERp72, ERp57 (or ERp60) and EFP1. PDI, ERp72 and ERp57 are endoplasmic reticulum (ER)-resident eukaryotic proteins involved in oxidative protein folding. They are oxidases, catalyzing the formation of disulfide bonds of newly synthesized polypeptides in the ER. They also exhibit reductase activity in acting as isomerases to correct any non-native disulfide bonds, as well as chaperone activity to prevent protein aggregation and facilitate the folding of newly synthesized proteins. PDI and ERp57 have the abb'a' domain structure (where a and a' are redox active TRX domains while b and b' are redox inactive TRX-like domains). PDI also contains an acidic region (c domain) after the a' domain that is absent in ERp57. ERp72 has an additional a domain at the N-terminus (a"abb'a' domain structure). ERp57 interacts with the lectin chaperones, calnexin and calreticulin, and specifically promotes the oxidative folding of glycoproteins, while PDI shows a wider substrate specificity. ERp72 associates with several ER chaperones and folding factors to form complexes in the ER that bind nascent proteins. EFP1 is a binding partner protein of thyroid oxidase, which is responsible for the generation of hydrogen peroxide, a crucial substrate of thyroperoxidase, which functions to iodinate thyroglobulin and synthesize thyroid hormones.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617  382 PVKVVVADNVHDVVFKSGKNVLIEFYAPWCGHCKKLAPILDEAAATLQSEEDVVIAKMDATENDVPGEFDVQGYPTLYFV 461
Cdd:cd02995   1 PVKVVVGKNFDEVVLDSDKDVLVEFYAPWCGHCKALAPIYEELAEKLKGDDNVVIAKMDATANDVPSEFVVDGFPTILFF 80

                        90       100
                ....*....|....*....|....*
gi 1709617  462 tPSGKK---VSYEGGRTADEIVDYI 483
Cdd:cd02995  81 -PAGDKsnpIKYEGDRTLEDLIKFI 104

Chaperedoxin CnoX, contains thioredoxin-like and TPR-like domains, YbbN/TrxSC family [Posttranslational modification, protein turnover, chaperones];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617   40 VLTLHADNFDDAIGQ-HPFILVEFYAPWCGHCKSLAPEYEKAAQllsKHDPAIVLAKVDAndEKNKPLAGKYEVQGFPTL 118
Cdd:COG3118   2 VVELTDENFEEEVLEsDKPVLVDFWAPWCGPCKMLAPVLEELAA---EYGGKVKFVKVDV--DENPELAAQFGVRSIPTL 76

                        90       100       110
                ....*....|....*....|....*....|
gi 1709617  119 KIFRNgGKSIQEYKGPREAEGIVEYLKKQV 148
Cdd:COG3118  77 LLFKD-GQPVDRFVGALPKEQLREFLDKVL 105

protein disulfide isomerase, eukaryotic; This model represents eukaryotic protein disulfide isomerases retained in the endoplasmic reticulum (ER) and closely related forms. Some members have been assigned alternative or additional functions such as prolyl 4-hydroxylase and dolichyl-diphosphooligosaccharide-protein glycotransferase. Members of this family have at least two protein-disulfide domains, each similar to thioredoxin but with the redox-active disulfide in the motif PWCGHCK, and an ER retention signal at the extreme C-terminus (KDEL, HDEL, and similar motifs).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617     40 VLTLHADNFDDAIGQHPFILVEFYAPWCGHCKSLAPEYEKAAQLLSKHDPAIVLAKVDANDEKnkPLAGKYEVQGFPTLK 119
Cdd:TIGR01130   3 VLVLTKDNFDDFIKSHEFVLVEFYAPWCGHCKSLAPEYEKAADELKKKGPPIKLAKVDATEEK--DLAQKYGVSGYPTLK 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617    120 IFRNGGKSIQEYKGPREAEGIVEYLKKQVGPASKEIKAPEDAT-YLEDGKIHIVGVFTEFSGPEFTNFLEVAEKLRSYYD 198
Cdd:TIGR01130  81 IFRNGEDSVSDYNGPRDADGIVKYMKKQSGPAVKEIETVADLEaFLADDDVVVIGFFKDLDSELNDTFLSVAEKLRDVYF 160

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617    199 -FGHTVHANHLPRGDAAVERPVVRLFKPFDE---LVVDSKDFDVSALEKFIDASSTPKVVIFDKNPDNHPYLLKFFQSNA 274
Cdd:TIGR01130 161 fFAHSSDVAAFAKLGAFPDSVVLFKPKDEDEkfsKVDGEMDTDVSDLEKFIRAESLPLVGEFTQETAAKYFESGPLVVLY 240

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617    275 pkamLFLNFSTGPFESFKSAYYGAVEEFSGKDVKFLIGDIESSQGAFQYFGLKVDQAPLILIQDGDS-KKFLKEHVEAG- 352
Cdd:TIGR01130 241 ----YNVDESLDPFEELRNRFLEAAKKFRGKFVNFAVADEEDFGRELEYFGLKAEKFPAVAIQDLEGnKKYPMDQEEFSs 316

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617    353 -QIVAWLKDYFDGKLTPFRKSEPIPEANNEPVKVVVADNVHDVVFKSGKNVLIEFYAPWCGHCKKLAPILDEAAATLQS- 430
Cdd:TIGR01130 317 eNLEAFVKDFLDGKLKPYLKSEPIPEDDEGPVKVLVGKNFDEIVLDETKDVLVEFYAPWCGHCKNLAPIYEELAEKYKDa 396

                         410       420       430       440       450       460
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1709617    431 EEDVVIAKMDATENDVPGeFDVQGYPTLYFVTPSGKK--VSYEGGRTADEIVDYIRKNKETAGQ 492
Cdd:TIGR01130 397 ESDVVIAKMDATANDVPP-FEVEGFPTIKFVPAGKKSepVPYDGDRTLEDFSKFIAKHATFPLE 459

PDIa family, C-terminal TRX domain (a') subfamily; composed of the C-terminal redox active a' domains of PDI, ERp72, ERp57 (or ERp60) and EFP1. PDI, ERp72 and ERp57 are endoplasmic reticulum (ER)-resident eukaryotic proteins involved in oxidative protein folding. They are oxidases, catalyzing the formation of disulfide bonds of newly synthesized polypeptides in the ER. They also exhibit reductase activity in acting as isomerases to correct any non-native disulfide bonds, as well as chaperone activity to prevent protein aggregation and facilitate the folding of newly synthesized proteins. PDI and ERp57 have the abb'a' domain structure (where a and a' are redox active TRX domains while b and b' are redox inactive TRX-like domains). PDI also contains an acidic region (c domain) after the a' domain that is absent in ERp57. ERp72 has an additional a domain at the N-terminus (a"abb'a' domain structure). ERp57 interacts with the lectin chaperones, calnexin and calreticulin, and specifically promotes the oxidative folding of glycoproteins, while PDI shows a wider substrate specificity. ERp72 associates with several ER chaperones and folding factors to form complexes in the ER that bind nascent proteins. EFP1 is a binding partner protein of thyroid oxidase, which is responsible for the generation of hydrogen peroxide, a crucial substrate of thyroperoxidase, which functions to iodinate thyroglobulin and synthesize thyroid hormones.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617  382 PVKVVVADNVHDVVFKSGKNVLIEFYAPWCGHCKKLAPILDEAAATLQSEEDVVIAKMDATENDVPGEFDVQGYPTLYFV 461
Cdd:cd02995   1 PVKVVVGKNFDEVVLDSDKDVLVEFYAPWCGHCKALAPIYEELAEKLKGDDNVVIAKMDATANDVPSEFVVDGFPTILFF 80

                        90       100
                ....*....|....*....|....*
gi 1709617  462 tPSGKK---VSYEGGRTADEIVDYI 483
Cdd:cd02995  81 -PAGDKsnpIKYEGDRTLEDLIKFI 104

Protein Disulfide Isomerase (PDIa) family, redox active TRX domains; composed of eukaryotic proteins involved in oxidative protein folding in the endoplasmic reticulum (ER) by acting as catalysts and folding assistants. Members of this family include PDI and PDI-related proteins like ERp72, ERp57 (or ERp60), ERp44, P5, PDIR, ERp46 and the transmembrane PDIs. PDI, ERp57, ERp72, P5, PDIR and ERp46 are all oxidases, catalyzing the formation of disulfide bonds of newly synthesized polypeptides in the ER. They also exhibit reductase activity in acting as isomerases to correct any non-native disulfide bonds, as well as chaperone activity to prevent protein aggregation and facilitate the folding of newly synthesized proteins. These proteins usually contain multiple copies of a redox active TRX (a) domain containing a CXXC motif, and may also contain one or more redox inactive TRX-like (b) domains. Only one a domain is required for the oxidase function but multiple copies are necessary for the isomerase function. The different types of PDIs may show different substrate specificities and tissue-specific expression, or may be induced by stress. PDIs are in their reduced form at steady state and are oxidized to the active form by Ero1, which is localized in the ER through ERp44. Some members of this family also contain a DnaJ domain in addition to the redox active a domains; examples are ERdj5 and Pfj2. Also included in the family is the redox inactive N-terminal TRX-like domain of ERp29.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617   41 LTLHADNFDDAIGQHPFILVEFYAPWCGHCKSLAPEYEKAAQLLsKHDPAIVLAKVDAndEKNKPLAGKYEVQGFPTLKI 120
Cdd:cd02961   1 VELTDDNFDELVKDSKDVLVEFYAPWCGHCKALAPEYEKLAKEL-KGDGKVVVAKVDC--TANNDLCSEYGVRGYPTIKL 77

                        90       100
                ....*....|....*....|....
gi 1709617  121 FRNGGKSIQEYKGPREAEGIVEYL 144
Cdd:cd02961  78 FPNGSKEPVKYEGPRTLESLVEFI 101

PDIa family, endoplasmic reticulum protein 38 (ERp38) subfamily; composed of proteins similar to the P5-like protein first isolated from alfalfa, which contains two redox active TRX (a) domains at the N-terminus, like human P5, and a C-terminal domain with homology to the C-terminal domain of ERp29, unlike human P5. The cDNA clone of this protein (named G1) was isolated from an alfalfa cDNA library by screening with human protein disulfide isomerase (PDI) cDNA. The G1 protein is constitutively expressed in all major organs of the plant and its expression is induced by treatment with tunicamycin, indicating that it may be a glucose-regulated protein. The G1 homolog in the eukaryotic social amoeba Dictyostelium discoideum is also described as a P5-like protein, which is located in the endoplasmic reticulum (ER) despite the absence of an ER-retrieval signal. G1 homologs from Aspergillus niger and Neurospora crassa have also been characterized, and are named TIGA and ERp38, respectively. Also included in the alignment is an atypical PDI from Leishmania donovani containing a single a domain, and the C-terminal a domain of a P5-like protein from Entamoeba histolytica.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617   40 VLTLHADNFDDAIGQ-HPFILVEFYAPWCGHCKSLAPEYEKAAQLLsKHDPAIVLAKVDAnDEKNKPLAGKYEVQGFPTL 118
Cdd:cd02998   2 VVELTDSNFDKVVGDdKKDVLVEFYAPWCGHCKNLAPEYEKLAAVF-ANEDDVVIAKVDA-DEANKDLAKKYGVSGFPTL 79

                        90       100
                ....*....|....*....|....*.
gi 1709617  119 KIFRNGGKSIQEYKGPREAEGIVEYL 144
Cdd:cd02998  80 KFFPKGSTEPVKYEGGRDLEDLVKFV 105

Protein Disulfide Isomerase (PDIa) family, redox active TRX domains; composed of eukaryotic proteins involved in oxidative protein folding in the endoplasmic reticulum (ER) by acting as catalysts and folding assistants. Members of this family include PDI and PDI-related proteins like ERp72, ERp57 (or ERp60), ERp44, P5, PDIR, ERp46 and the transmembrane PDIs. PDI, ERp57, ERp72, P5, PDIR and ERp46 are all oxidases, catalyzing the formation of disulfide bonds of newly synthesized polypeptides in the ER. They also exhibit reductase activity in acting as isomerases to correct any non-native disulfide bonds, as well as chaperone activity to prevent protein aggregation and facilitate the folding of newly synthesized proteins. These proteins usually contain multiple copies of a redox active TRX (a) domain containing a CXXC motif, and may also contain one or more redox inactive TRX-like (b) domains. Only one a domain is required for the oxidase function but multiple copies are necessary for the isomerase function. The different types of PDIs may show different substrate specificities and tissue-specific expression, or may be induced by stress. PDIs are in their reduced form at steady state and are oxidized to the active form by Ero1, which is localized in the ER through ERp44. Some members of this family also contain a DnaJ domain in addition to the redox active a domains; examples are ERdj5 and Pfj2. Also included in the family is the redox inactive N-terminal TRX-like domain of ERp29.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617  384 KVVVADNVHDVVFKSgKNVLIEFYAPWCGHCKKLAPILDEAAATLQSEEDVVIAKMDATEN-DVPGEFDVQGYPTLYFVT 462
Cdd:cd02961   1 VELTDDNFDELVKDS-KDVLVEFYAPWCGHCKALAPEYEKLAKELKGDGKVVVAKVDCTANnDLCSEYGVRGYPTIKLFP 79

                        90       100
                ....*....|....*....|..
gi 1709617  463 PSGKK-VSYEGGRTADEIVDYI 483
Cdd:cd02961  80 NGSKEpVKYEGPRTLESLVEFI 101

PDIa family, P5 subfamily; composed of eukaryotic proteins similar to human P5, a PDI-related protein with a domain structure of aa'b (where a and a' are redox active TRX domains and b is a redox inactive TRX-like domain). Like PDI, P5 is located in the endoplasmic reticulum (ER) and displays both isomerase and chaperone activities, which are independent of each other. Compared to PDI, the isomerase and chaperone activities of P5 are lower. The first cysteine in the CXXC motif of both redox active domains in P5 is necessary for isomerase activity. The P5 gene was first isolated as an amplified gene from a hydroxyurea-resistant hamster cell line. The zebrafish P5 homolog has been implicated to play a critical role in establishing left/right asymmetries in the embryonic midline. Some members of this subfamily are P5-like proteins containing only one redox active TRX domain.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617   40 VLTLHADNFDDAIGQH-PFILVEFYAPWCGHCKSLAPEYEKAAQLLSkhdpAIV-LAKVDAndEKNKPLAGKYEVQGFPT 117
Cdd:cd03001   2 VVELTDSNFDKKVLNSdDVWLVEFYAPWCGHCKNLAPEWKKAAKALK----GIVkVGAVDA--DVHQSLAQQYGVRGFPT 75

                        90       100
                ....*....|....*....|....*
gi 1709617  118 LKIFRNGGKSIQEYKGPREAEGIVE 142
Cdd:cd03001  76 IKVFGAGKNSPQDYQGGRTAKAIVS 100

Thioredoxin; Thioredoxins are small enzymes that participate in redox reactions, via the reversible oxidation of an active centre disulfide bond. Some members with only the active site are not separated from the noise.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617    382 PVKVVVADNVHDVVFKSGKNVLIEFYAPWCGHCKKLAPILDEAAATLQseEDVVIAKMDATEN-DVPGEFDVQGYPTLYF 460
Cdd:pfam00085   1 VVVVLTDANFDEVVQKSSKPVLVDFYAPWCGPCKMLAPEYEELAQEYK--GNVVFAKVDVDENpDLASKYGVRGYPTLIF 78

                          90       100
                  ....*....|....*....|....*
gi 1709617    461 VTPSGKKVSYEGGRTADEIVDYIRK 485
Cdd:pfam00085  79 FKNGQPVDDYVGARPKDALAAFLKA 103

PDIa family, endoplasmic reticulum protein 46 (ERp46) subfamily; ERp46 is an ER-resident protein containing three redox active TRX domains. Yeast complementation studies show that ERp46 can substitute for protein disulfide isomerase (PDI) function in vivo. It has been detected in many tissues, however, transcript and protein levels do not correlate in all tissues, suggesting regulation at a posttranscriptional level. An identical protein, named endoPDI, has been identified as an endothelial PDI that is highly expressed in the endothelium of tumors and hypoxic lesions. It has a protective effect on cells exposed to hypoxia.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617   40 VLTLHADNFDDAI--GQHpfiLVEFYAPWCGHCKSLAPEYEKAAQLLSKHDPAIVLAKVDANDEKNkpLAGKYEVQGFPT 117
Cdd:cd03005   2 VLELTEDNFDHHIaeGNH---FVKFFAPWCGHCKRLAPTWEQLAKKFNNENPSVKIAKVDCTQHRE--LCSEFQVRGYPT 76

                        90       100
                ....*....|....*....|....*..
gi 1709617  118 LKIFRNGGKSIqEYKGPREAEGIVEYL 144
Cdd:cd03005  77 LLLFKDGEKVD-KYKGTRDLDSLKEFV 102

Chaperedoxin CnoX, contains thioredoxin-like and TPR-like domains, YbbN/TrxSC family [Posttranslational modification, protein turnover, chaperones];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617   40 VLTLHADNFDDAIGQ-HPFILVEFYAPWCGHCKSLAPEYEKAAQllsKHDPAIVLAKVDAndEKNKPLAGKYEVQGFPTL 118
Cdd:COG3118   2 VVELTDENFEEEVLEsDKPVLVDFWAPWCGPCKMLAPVLEELAA---EYGGKVKFVKVDV--DENPELAAQFGVRSIPTL 76

                        90       100       110
                ....*....|....*....|....*....|
gi 1709617  119 KIFRNgGKSIQEYKGPREAEGIVEYLKKQV 148
Cdd:COG3118  77 LLFKD-GQPVDRFVGALPKEQLREFLDKVL 105

PDIa family, P5 subfamily; composed of eukaryotic proteins similar to human P5, a PDI-related protein with a domain structure of aa'b (where a and a' are redox active TRX domains and b is a redox inactive TRX-like domain). Like PDI, P5 is located in the endoplasmic reticulum (ER) and displays both isomerase and chaperone activities, which are independent of each other. Compared to PDI, the isomerase and chaperone activities of P5 are lower. The first cysteine in the CXXC motif of both redox active domains in P5 is necessary for isomerase activity. The P5 gene was first isolated as an amplified gene from a hydroxyurea-resistant hamster cell line. The zebrafish P5 homolog has been implicated to play a critical role in establishing left/right asymmetries in the embryonic midline. Some members of this subfamily are P5-like proteins containing only one redox active TRX domain.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617  382 PVKVVVADNVHDVVFKSGKNVLIEFYAPWCGHCKKLAPILDEAAATLQSEedVVIAKMDATEND-VPGEFDVQGYPTL-Y 459
Cdd:cd03001   1 DVVELTDSNFDKKVLNSDDVWLVEFYAPWCGHCKNLAPEWKKAAKALKGI--VKVGAVDADVHQsLAQQYGVRGFPTIkV 78

                        90       100
                ....*....|....*....|..
gi 1709617  460 FVTPSGKKVSYEGGRTADEIVD 481
Cdd:cd03001  79 FGAGKNSPQDYQGGRTAKAIVS 100

Chaperedoxin CnoX, contains thioredoxin-like and TPR-like domains, YbbN/TrxSC family [Posttranslational modification, protein turnover, chaperones];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617  383 VKVVVADNVHDVVFKSGKNVLIEFYAPWCGHCKKLAPILDEAAATLQseEDVVIAKMDATEN-DVPGEFDVQGYPTLYFV 461
Cdd:COG3118   2 VVELTDENFEEEVLESDKPVLVDFWAPWCGPCKMLAPVLEELAAEYG--GKVKFVKVDVDENpELAAQFGVRSIPTLLLF 79

                        90       100
                ....*....|....*....|....*.
gi 1709617  462 TpSGKKV-SYEGGRTADEIVDYIRKN 486
Cdd:COG3118  80 K-DGQPVdRFVGALPKEQLREFLDKV 104

PDIa family, endoplasmic reticulum protein 44 (ERp44) subfamily; ERp44 is an ER-resident protein, induced during stress, involved in thiol-mediated ER retention. It contains an N-terminal TRX domain, similar to that of PDIa, with a CXFS motif followed by two redox inactive TRX-like domains, homologous to the b and b' domains of PDI. The CXFS motif in the N-terminal domain allows ERp44 to form stable reversible mixed disulfides with its substrates. Through this activity, ERp44 mediates the ER localization of Ero1alpha, a protein that oxidizes protein disulfide isomerases into their active form. ERp44 also prevents the secretion of unassembled cargo protein with unpaired cysteines. It also modulates the activity of inositol 1,4,5-triphosphate type I receptor (IP3R1), an intracellular channel protein that mediates calcium release from the ER to the cytosol.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617   40 VLTLHADNFDDAIGQHPFILVEFYAPWCGHCKSLAPEYEKAAQLLSKHDP---AIVLAKVDANDEKNkpLAGKYEVQGFP 116
Cdd:cd02996   3 IVSLTSGNIDDILQSAELVLVNFYADWCRFSQMLHPIFEEAAAKIKEEFPdagKVVWGKVDCDKESD--IADRYRINKYP 80

                        90       100
                ....*....|....*....|....*...
gi 1709617  117 TLKIFRNGGKSIQEYKGPREAEGIVEYL 144
Cdd:cd02996  81 TLKLFRNGMMMKREYRGQRSVEALAEFV 108

PDIa family, TMX3 subfamily; composed of eukaryotic proteins similar to human TMX3, a TRX related transmembrane protein containing one redox active TRX domain at the N-terminus and a classical ER retrieval sequence for type I transmembrane proteins at the C-terminus. The TMX3 transcript is found in a variety of tissues with the highest levels detected in skeletal muscle and the heart. In vitro, TMX3 showed oxidase activity albeit slightly lower than that of protein disulfide isomerase.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617  403 LIEFYAPWCGHCKKLAPILDEAAATLQ-SEEDVVIAKMDATE-NDVPGEFDVQGYPTLYFVTpSGKKVSYEGGRTADEIV 480
Cdd:cd03000  19 LVDFYAPWCGHCKKLEPVWNEVGAELKsSGSPVRVGKLDATAySSIASEFGVRGYPTIKLLK-GDLAYNYRGPRTKDDIV 97

                ..
gi 1709617  481 DY 482
Cdd:cd03000  98 EF 99

PDIa family, TMX3 subfamily; composed of eukaryotic proteins similar to human TMX3, a TRX related transmembrane protein containing one redox active TRX domain at the N-terminus and a classical ER retrieval sequence for type I transmembrane proteins at the C-terminus. The TMX3 transcript is found in a variety of tissues with the highest levels detected in skeletal muscle and the heart. In vitro, TMX3 showed oxidase activity albeit slightly lower than that of protein disulfide isomerase.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617   59 LVEFYAPWCGHCKSLAPEYEKAAQLLSKHDPAIVLAKVDANdeKNKPLAGKYEVQGFPTLKIFRNGgkSIQEYKGPREAE 138
Cdd:cd03000  19 LVDFYAPWCGHCKKLEPVWNEVGAELKSSGSPVRVGKLDAT--AYSSIASEFGVRGYPTIKLLKGD--LAYNYRGPRTKD 94

                ....*...
gi 1709617  139 GIVEYLKK 146
Cdd:cd03000  95 DIVEFANR 102

thioredoxin; Several proteins, such as protein disulfide isomerase, have two or more copies of a domain closely related to thioredoxin. This model is designed to recognize authentic thioredoxin, a small protein that should be hit exactly once by this model. Any protein that hits once with a score greater than the second (per domain) trusted cutoff may be taken as thioredoxin. [Energy metabolism, Electron transport]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617    388 ADNVHDVVFKSGKNVLIEFYAPWCGHCKKLAPILDEAAATLQSeeDVVIAKMDATEN-DVPGEFDVQGYPTLYFvTPSGK 466
Cdd:TIGR01068   3 DANFDETIASSDKPVLVDFWAPWCGPCKMIAPILEELAKEYEG--KVKFVKLNVDENpDIAAKYGIRSIPTLLL-FKNGK 79

                          90       100
                  ....*....|....*....|..
gi 1709617    467 KVS-YEGGRTADEIVDYIRKNK 487
Cdd:TIGR01068  80 EVDrSVGALPKAALKQLINKNL 101

TRX family; composed of two groups: Group I, which includes proteins that exclusively encode a TRX domain; and Group II, which are composed of fusion proteins of TRX and additional domains. Group I TRX is a small ancient protein that alter the redox state of target proteins via the reversible oxidation of an active site dithiol, present in a CXXC motif, partially exposed at the protein's surface. TRX reduces protein disulfide bonds, resulting in a disulfide bond at its active site. Oxidized TRX is converted to the active form by TRX reductase, using reducing equivalents derived from either NADPH or ferredoxins. By altering their redox state, TRX regulates the functions of at least 30 target proteins, some of which are enzymes and transcription factors. It also plays an important role in the defense against oxidative stress by directly reducing hydrogen peroxide and certain radicals, and by serving as a reductant for peroxiredoxins. At least two major types of functional TRXs have been reported in most organisms; in eukaryotes, they are located in the cytoplasm and the mitochondria. Higher plants contain more types (at least 20 TRX genes have been detected in the genome of Arabidopsis thaliana), two of which (types f amd m) are located in the same compartment, the chloroplast. Also included in the alignment are TRX-like domains which show sequence homology to TRX but do not contain the redox active CXXC motif. Group II proteins, in addition to either a redox active TRX or a TRX-like domain, also contain additional domains, which may or may not possess homology to known proteins.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617  397 KSGKNVLIEFYAPWCGHCKKLAPILDEAAATlqsEEDVVIAKMDATEN-DVPGEFDVQGYPTLYFvtpsgkkvsYEGGRT 475
Cdd:cd02947   8 KSAKPVVVDFWAPWCGPCKAIAPVLEELAEE---YPKVKFVKVDVDENpELAEEYGVRSIPTFLF---------FKNGKE 75

                        90
                ....*....|..
gi 1709617  476 ADEIVDYIRKNK 487
Cdd:cd02947  76 VDRVVGADPKEE 87

disulphide isomerase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617    58 ILVEFYAPWCGHCKSLAPEYEKAAQLLSKHDpAIVLAKVD--ANDeknKPLAGkYEVQGFPTLKIFRNGGKSIQEYKGPR 135
Cdd:PTZ00102 378 VLLEIYAPWCGHCKNLEPVYNELGEKYKDND-SIIVAKMNgtANE---TPLEE-FSWSAFPTILFVKAGERTPIPYEGER 452

                         90       100
                 ....*....|....*....|....
gi 1709617   136 EAEGIVEYLKKQVGPASKEIKAPE 159
Cdd:PTZ00102 453 TVEGFKEFVNKHATNPFEDDTHEE 476

thioredoxin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617    48 FDDAIGQHPFILVEFYAPWCGHCKSLAPEYEKaaqlLSKHDPAIVLAKVDANDEKNkpLAGKYEVQGFPTLKIFRNgGKS 127
Cdd:PTZ00051  11 FESTLSQNELVIVDFYAEWCGPCKRIAPFYEE----CSKEYTKMVFVKVDVDELSE--VAEKENITSMPTFKVFKN-GSV 83

                 ....*.
gi 1709617   128 IQEYKG 133
Cdd:PTZ00051  84 VDTLLG 89

Protein Disulfide Isomerase (PDIb) family, redox inactive TRX-like domain b; composed of eukaryotic proteins involved in oxidative protein folding in the endoplasmic reticulum (ER) by acting as catalysts and folding assistants. Members of this family include PDI, calsequestrin and other PDI-related proteins like ERp72, ERp57, ERp44 and PDIR. PDI, ERp57 (or ERp60), ERp72 and PDIR are all oxidases, catalyzing the formation of disulfide bonds of newly synthesized polypeptides in the ER. They also exhibit reductase activity in acting as isomerases to correct any non-native disulfide bonds, as well as chaperone activity to prevent protein aggregation and facilitate the folding of newly synthesized proteins. These proteins contain multiple copies of a redox active TRX (a) domain containing a CXXC motif, and one or more redox inactive TRX-like (b) domains. The molecular structure of PDI is abb'a'. Also included in this family is the PDI-related protein ERp27, which contains only redox-inactive TRX-like (b and b') domains. The redox inactive b domains are implicated in substrate recognition.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1709617  152 SKEIKAPEDATYLEDG-KIHIVGVFTEFSGPEFTNFLEVAEKLRSYYDFGHTVHANHLPRGDaaVERPVVRLFKPFDELV 230
Cdd:cd02981   1 VKELTSKEELEKFLDKdDVVVVGFFKDEESEEYKTFEKVAESLRDDYGFGHTSDKEVAKKLK--VKPGSVVLFKPFEEEP 78

                        90
                ....*....|....*.
gi 1709617  231 VD-SKDFDVSALEKFI 245
Cdd:cd02981  79 VEyDGEFTEESLVEFI 94