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 94966757    42 DGILVLSRHTLGLALREHPALLVEFYAPWCGHCQALAPEYSKAAAVLAAESMVVTLAKVDGPAQRELAEEFGVTEYPTLK 121
Cdd:TIGR01130   1 EDVLVLTKDNFDDFIKSHEFVLVEFYAPWCGHCKSLAPEYEKAADELKKKGPPIKLAKVDATEEKDLAQKYGVSGYPTLK 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 94966757   122 FFRNGNRThPEEYTGPRDAEGIAEWLRRRVGPSAMRLEDEAAAQALIGGRDLVVIGFFQDLQDEDVATFLALAQDALDMT 201
Cdd:TIGR01130  81 IFRNGEDS-VSDYNGPRDADGIVKYMKKQSGPAVKEIETVADLEAFLADDDVVVIGFFKDLDSELNDTFLSVAEKLRDVY 159

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 94966757   202 FGL--TDRPRLFQQFGLTKDTVVLFKKFDEGRADFPVDEELGLDLGDLSRFLVTHSMRLVTEFNSQTSAKIFAARILNHL 279
Cdd:TIGR01130 160 FFFahSSDVAAFAKLGAFPDSVVLFKPKDEDEKFSKVDGEMDTDVSDLEKFIRAESLPLVGEFTQETAAKYFESGPLVVL 239

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 94966757   280 LLFVNQTLAAHRELLAGFGEAAPRFRGQVLFVVVDVAADNEHVLQYFGLKAEAAPTLRLVNLETTKKYAPvDGGPVTAAS 359
Cdd:TIGR01130 240 YYNVDESLDPFEELRNRFLEAAKKFRGKFVNFAVADEEDFGRELEYFGLKAEKFPAVAIQDLEGNKKYPM-DQEEFSSEN 318

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 94966757   360 ITAFCHAVLNGQVKPYLLSQEIPPDwDQRPVKTLVGKNFEQVAFDETKNVFVKFYAPWCTHCKEMAPAWEALAEKYQDHE 439
Cdd:TIGR01130 319 LEAFVKDFLDGKLKPYLKSEPIPED-DEGPVKVLVGKNFDEIVLDETKDVLVEFYAPWCGHCKNLAPIYEELAEKYKDAE 397

                         410       420       430       440       450
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 94966757   440 -DIIIAELDATANELDAFAVHGFPTLKYFPAGPGRKVIEYKSTRDLETFSKFLDNGGVL 497
Cdd:TIGR01130 398 sDVVIAKMDATANDVPPFEVEGFPTIKFVPAGKKSEPVPYDGDRTLEDFSKFIAKHATF 456

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 94966757    42 DGILVLSRHTLGLALREHPALLVEFYAPWCGHCQALAPEYSKAAAVLAAESMVVTLAKVDGPAQRELAEEFGVTEYPTLK 121
Cdd:TIGR01130   1 EDVLVLTKDNFDDFIKSHEFVLVEFYAPWCGHCKSLAPEYEKAADELKKKGPPIKLAKVDATEEKDLAQKYGVSGYPTLK 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 94966757   122 FFRNGNRThPEEYTGPRDAEGIAEWLRRRVGPSAMRLEDEAAAQALIGGRDLVVIGFFQDLQDEDVATFLALAQDALDMT 201
Cdd:TIGR01130  81 IFRNGEDS-VSDYNGPRDADGIVKYMKKQSGPAVKEIETVADLEAFLADDDVVVIGFFKDLDSELNDTFLSVAEKLRDVY 159

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 94966757   202 FGL--TDRPRLFQQFGLTKDTVVLFKKFDEGRADFPVDEELGLDLGDLSRFLVTHSMRLVTEFNSQTSAKIFAARILNHL 279
Cdd:TIGR01130 160 FFFahSSDVAAFAKLGAFPDSVVLFKPKDEDEKFSKVDGEMDTDVSDLEKFIRAESLPLVGEFTQETAAKYFESGPLVVL 239

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 94966757   280 LLFVNQTLAAHRELLAGFGEAAPRFRGQVLFVVVDVAADNEHVLQYFGLKAEAAPTLRLVNLETTKKYAPvDGGPVTAAS 359
Cdd:TIGR01130 240 YYNVDESLDPFEELRNRFLEAAKKFRGKFVNFAVADEEDFGRELEYFGLKAEKFPAVAIQDLEGNKKYPM-DQEEFSSEN 318

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 94966757   360 ITAFCHAVLNGQVKPYLLSQEIPPDwDQRPVKTLVGKNFEQVAFDETKNVFVKFYAPWCTHCKEMAPAWEALAEKYQDHE 439
Cdd:TIGR01130 319 LEAFVKDFLDGKLKPYLKSEPIPED-DEGPVKVLVGKNFDEIVLDETKDVLVEFYAPWCGHCKNLAPIYEELAEKYKDAE 397

                         410       420       430       440       450
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 94966757   440 -DIIIAELDATANELDAFAVHGFPTLKYFPAGPGRKVIEYKSTRDLETFSKFLDNGGVL 497
Cdd:TIGR01130 398 sDVVIAKMDATANDVPPFEVEGFPTIKFVPAGKKSEPVPYDGDRTLEDFSKFIAKHATF 456

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 94966757 389 PVKTLVGKNFEQVAFDETKNVFVKFYAPWCTHCKEMAPAWEALAEKYQDHEDIIIAELDATANEL-DAFAVHGFPTLKYF 467
Cdd:cd02995   1 PVKVVVGKNFDEVVLDSDKDVLVEFYAPWCGHCKALAPIYEELAEKLKGDDNVVIAKMDATANDVpSEFVVDGFPTILFF 80

                        90       100
                ....*....|....*....|....
gi 94966757 468 PAGPGRKVIEYKSTRDLETFSKFL 491
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 94966757  56 LREHPALLVEFYAPWCGHCQALAPEYSKAAAVLAAEsmvVTLAKVDGPAQRELAEEFGVTEYPTLKFFRNGNRThpEEYT 135
Cdd:COG3118  15 LESDKPVLVDFWAPWCGPCKMLAPVLEELAAEYGGK---VKFVKVDVDENPELAAQFGVRSIPTLLLFKDGQPV--DRFV 89

                        90
                ....*....|....
gi 94966757 136 GPRDAEGIAEWLRR 149
Cdd:COG3118  90 GALPKEQLREFLDK 103

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 94966757    42 DGILVLSRHTLGLALREHPALLVEFYAPWCGHCQALAPEYSKAAAVLAAESMVVTLAKVDGPAQRELAEEFGVTEYPTLK 121
Cdd:TIGR01130   1 EDVLVLTKDNFDDFIKSHEFVLVEFYAPWCGHCKSLAPEYEKAADELKKKGPPIKLAKVDATEEKDLAQKYGVSGYPTLK 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 94966757   122 FFRNGNRThPEEYTGPRDAEGIAEWLRRRVGPSAMRLEDEAAAQALIGGRDLVVIGFFQDLQDEDVATFLALAQDALDMT 201
Cdd:TIGR01130  81 IFRNGEDS-VSDYNGPRDADGIVKYMKKQSGPAVKEIETVADLEAFLADDDVVVIGFFKDLDSELNDTFLSVAEKLRDVY 159

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 94966757   202 FGL--TDRPRLFQQFGLTKDTVVLFKKFDEGRADFPVDEELGLDLGDLSRFLVTHSMRLVTEFNSQTSAKIFAARILNHL 279
Cdd:TIGR01130 160 FFFahSSDVAAFAKLGAFPDSVVLFKPKDEDEKFSKVDGEMDTDVSDLEKFIRAESLPLVGEFTQETAAKYFESGPLVVL 239

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 94966757   280 LLFVNQTLAAHRELLAGFGEAAPRFRGQVLFVVVDVAADNEHVLQYFGLKAEAAPTLRLVNLETTKKYAPvDGGPVTAAS 359
Cdd:TIGR01130 240 YYNVDESLDPFEELRNRFLEAAKKFRGKFVNFAVADEEDFGRELEYFGLKAEKFPAVAIQDLEGNKKYPM-DQEEFSSEN 318

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 94966757   360 ITAFCHAVLNGQVKPYLLSQEIPPDwDQRPVKTLVGKNFEQVAFDETKNVFVKFYAPWCTHCKEMAPAWEALAEKYQDHE 439
Cdd:TIGR01130 319 LEAFVKDFLDGKLKPYLKSEPIPED-DEGPVKVLVGKNFDEIVLDETKDVLVEFYAPWCGHCKNLAPIYEELAEKYKDAE 397

                         410       420       430       440       450
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 94966757   440 -DIIIAELDATANELDAFAVHGFPTLKYFPAGPGRKVIEYKSTRDLETFSKFLDNGGVL 497
Cdd:TIGR01130 398 sDVVIAKMDATANDVPPFEVEGFPTIKFVPAGKKSEPVPYDGDRTLEDFSKFIAKHATF 456

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 94966757 389 PVKTLVGKNFEQVAFDETKNVFVKFYAPWCTHCKEMAPAWEALAEKYQDHEDIIIAELDATANEL-DAFAVHGFPTLKYF 467
Cdd:cd02995   1 PVKVVVGKNFDEVVLDSDKDVLVEFYAPWCGHCKALAPIYEELAEKLKGDDNVVIAKMDATANDVpSEFVVDGFPTILFF 80

                        90       100
                ....*....|....*....|....
gi 94966757 468 PAGPGRKVIEYKSTRDLETFSKFL 491
Cdd:cd02995  81 PAGDKSNPIKYEGDRTLEDLIKFI 104

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 94966757 390 VKTLVGKNFEQVAFDETKNVFVKFYAPWCTHCKEMAPAWEALAEKYQDHEDIIIAELDATANELDA---FAVHGFPTLKY 466
Cdd:cd02998   2 VVELTDSNFDKVVGDDKKDVLVEFYAPWCGHCKNLAPEYEKLAAVFANEDDVVIAKVDADEANKDLakkYGVSGFPTLKF 81

                        90       100
                ....*....|....*....|....*
gi 94966757 467 FPAGpGRKVIEYKSTRDLETFSKFL 491
Cdd:cd02998  82 FPKG-STEPVKYEGGRDLEDLVKFV 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 94966757  45 LVLSRHTLGLALREHPALLVEFYAPWCGHCQALAPEYSKAAAVLAAESmVVTLAKVDGPAQRELAEEFGVTEYPTLKFFR 124
Cdd:cd02961   1 VELTDDNFDELVKDSKDVLVEFYAPWCGHCKALAPEYEKLAKELKGDG-KVVVAKVDCTANNDLCSEYGVRGYPTIKLFP 79

                        90       100
                ....*....|....*....|...
gi 94966757 125 NGNRThPEEYTGPRDAEGIAEWL 147
Cdd:cd02961  80 NGSKE-PVKYEGPRTLESLVEFI 101

Thioredoxin-like domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 94966757   179 FQDLQDEDVATFLALAQD-ALDMTFGLTDRPRLFQQFGLTKDTVVLFKKFDEGRADFPVDEelgLDLGDLSRFLVTHSMR 257
Cdd:pfam13848   1 FEDKDSPLYEIFRKAAKElKGDVRFGITFSKEVADKYNIKEPAILLFRKFDEETVHYPGDS---INFEDLKKFIQKNCLP 77

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 94966757   258 LVTEFNSQTSAKIFAARILNHLLLFVNQTLAAHRELLAGFGEAAPRFRGQVLFVVVDvAADNEHVLQYFGLKAEAAPTLR 337
Cdd:pfam13848  78 LVREFTPENAEELFEEGIPPLLLLFLKKDDESTEEFKKALEKVAKKFRGKINFALVD-AKSFGRPLEYFGLSESDLPVIV 156

                         170       180
                  ....*....|....*....|....*...
gi 94966757   338 LVNLETTKKYAPvDGGPVTAASITAFCH 365
Cdd:pfam13848 157 IVDSFSHMYKYF-PSDEFSPESLKEFIN 183

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 94966757 390 VKTLVGKNFEQ-VAfdeTKNVFVKFYAPWCTHCKEMAPAWEALAEKY-QDHEDIIIAELDATA-NEL-DAFAVHGFPTLK 465
Cdd:cd03005   2 VLELTEDNFDHhIA---EGNHFVKFFAPWCGHCKRLAPTWEQLAKKFnNENPSVKIAKVDCTQhRELcSEFQVRGYPTLL 78

                        90       100
                ....*....|....*....|....*.
gi 94966757 466 YFPagPGRKVIEYKSTRDLETFSKFL 491
Cdd:cd03005  79 LFK--DGEKVDKYKGTRDLDSLKEFV 102

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 94966757  63 LVEFYAPWCGHCQALAPEYSKAAAVLAAesmVVTLAKVDGPAQRELAEEFGVTEYPTLKFFrNGNRTHPEEYTGPRDAEG 142
Cdd:cd03001  22 LVEFYAPWCGHCKNLAPEWKKAAKALKG---IVKVGAVDADVHQSLAQQYGVRGFPTIKVF-GAGKNSPQDYQGGRTAKA 97

                ....
gi 94966757 143 IAEW 146
Cdd:cd03001  98 IVSA 101

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 94966757   389 PVKTLVGKNFEQVAFDETKNVFVKFYAPWCTHCKEMAPAWEALAEKYQDheDIIIAELDATANELDA--FAVHGFPTLKY 466
Cdd:pfam00085   1 VVVVLTDANFDEVVQKSSKPVLVDFYAPWCGPCKMLAPEYEELAQEYKG--NVVFAKVDVDENPDLAskYGVRGYPTLIF 78

                          90       100
                  ....*....|....*....|....*.
gi 94966757   467 FPagPGRKVIEYKSTRDLETFSKFLD 492
Cdd:pfam00085  79 FK--NGQPVDDYVGARPKDALAAFLK 102

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 94966757  63 LVEFYAPWCGHCQALAPEYSKAAAVLAAESMVVtLAKVDGPAQrELAEEFGVTEYPTLKFFRNGNRTHPEEYTGPRDAEG 142
Cdd:cd02995  22 LVEFYAPWCGHCKALAPIYEELAEKLKGDDNVV-IAKMDATAN-DVPSEFVVDGFPTILFFPAGDKSNPIKYEGDRTLED 99

                ....*
gi 94966757 143 IAEWL 147
Cdd:cd02995 100 LIKFI 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 94966757  56 LREHPALLVEFYAPWCGHCQALAPEYSKAAAVLAAEsmvVTLAKVDGPAQRELAEEFGVTEYPTLKFFRNGNRThpEEYT 135
Cdd:COG3118  15 LESDKPVLVDFWAPWCGPCKMLAPVLEELAAEYGGK---VKFVKVDVDENPELAAQFGVRSIPTLLLFKDGQPV--DRFV 89

                        90
                ....*....|....
gi 94966757 136 GPRDAEGIAEWLRR 149
Cdd:COG3118  90 GALPKEQLREFLDK 103

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 94966757  55 ALREHPALLVEFYAPWCGHCQALAPEYSKaaavLAAESMVVTLAKVDGPAQRELAEEFGVTEYPTLKFFRNGNRTHpeEY 134
Cdd:cd02947   6 LIKSAKPVVVDFWAPWCGPCKAIAPVLEE----LAEEYPKVKFVKVDVDENPELAEEYGVRSIPTFLFFKNGKEVD--RV 79

                        90
                ....*....|...
gi 94966757 135 TGPRDAEGIAEWL 147
Cdd:cd02947  80 VGADPKEELEEFL 92

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 94966757  63 LVEFYAPWCGHCQALAPEYSKAAAVLAAESMVVTLAKVDGPAQRELAEEFGVTEYPTLKFFRNGnrtHPEEYTGPRDAEG 142
Cdd:cd03000  19 LVDFYAPWCGHCKKLEPVWNEVGAELKSSGSPVRVGKLDATAYSSIASEFGVRGYPTIKLLKGD---LAYNYRGPRTKDD 95

                ....*..
gi 94966757 143 IAEWLRR 149
Cdd:cd03000  96 IVEFANR 102

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 94966757 389 PVKTLVGKNFEQVAFDETKNVFVKFYAPWCTHCKEMAPAWEALAEKYQDheDIIIAELDATANELDA--FAVHGFPTLKY 466
Cdd:cd03001   1 DVVELTDSNFDKKVLNSDDVWLVEFYAPWCGHCKNLAPEWKKAAKALKG--IVKVGAVDADVHQSLAqqYGVRGFPTIKV 78

                        90
                ....*....|....*..
gi 94966757 467 FPAGPgRKVIEYKSTRD 483
Cdd:cd03001  79 FGAGK-NSPQDYQGGRT 94

PDIa family, Quiescin-sulfhydryl oxidase (QSOX) subfamily; QSOX is a eukaryotic protein containing an N-terminal redox active TRX domain, similar to that of PDI, and a small C-terminal flavin adenine dinucleotide (FAD)-binding domain homologous to the yeast ERV1p protein. QSOX oxidizes thiol groups to disulfides like PDI, however, unlike PDI, this oxidation is accompanied by the reduction of oxygen to hydrogen peroxide. QSOX is localized in high concentrations in cells with heavy secretory load and prefers peptides and proteins as substrates, not monothiols like glutathione. Inside the cell, QSOX is found in the endoplasmic reticulum and Golgi. The flow of reducing equivalents in a QSOX-catalyzed reaction goes from the dithiol substrate -> dithiol of the QSOX TRX domain -> dithiols of the QSOX ERV1p domain -> FAD -> oxygen.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 94966757  42 DGILVLSRHTLGLALREHP-ALLVEFYAPWCGHCQALAPEYSKAAAVLAAESMVVTLAKVD--GPAQRELAEEFGVTEYP 118
Cdd:cd02992   1 DPVIVLDAASFNSALLGSPsAWLVEFYASWCGHCRAFAPTWKKLARDLRKWRPVVRVAAVDcaDEENVALCRDFGVTGYP 80

                        90       100       110
                ....*....|....*....|....*....|....
gi 94966757 119 TLKFFRNGNRTHP--EEYTGP-RDAEGIAEWLRR 149
Cdd:cd02992  81 TLRYFPPFSKEATdgLKQEGPeRDVNELREALIL 114

PDIa family, Quiescin-sulfhydryl oxidase (QSOX) subfamily; QSOX is a eukaryotic protein containing an N-terminal redox active TRX domain, similar to that of PDI, and a small C-terminal flavin adenine dinucleotide (FAD)-binding domain homologous to the yeast ERV1p protein. QSOX oxidizes thiol groups to disulfides like PDI, however, unlike PDI, this oxidation is accompanied by the reduction of oxygen to hydrogen peroxide. QSOX is localized in high concentrations in cells with heavy secretory load and prefers peptides and proteins as substrates, not monothiols like glutathione. Inside the cell, QSOX is found in the endoplasmic reticulum and Golgi. The flow of reducing equivalents in a QSOX-catalyzed reaction goes from the dithiol substrate -> dithiol of the QSOX TRX domain -> dithiols of the QSOX ERV1p domain -> FAD -> oxygen.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 94966757 389 PVKTLVGKNFEQVAFDETKNVFVKFYAPWCTHCKEMAPAWEALAEKYQDHEDII-IAELDATANELDA----FAVHGFPT 463
Cdd:cd02992   2 PVIVLDAASFNSALLGSPSAWLVEFYASWCGHCRAFAPTWKKLARDLRKWRPVVrVAAVDCADEENVAlcrdFGVTGYPT 81

                ....*.
gi 94966757 464 LKYFPA 469
Cdd:cd02992  82 LRYFPP 87

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 94966757  63 LVEFYAPWCGHCQALAPEYSKAAAVL---AAESMVVTLAKVDGPAQRELAEEFGVTEYPTLKFFRNG---NRthpeEYTG 136
Cdd:cd02996  22 LVNFYADWCRFSQMLHPIFEEAAAKIkeeFPDAGKVVWGKVDCDKESDIADRYRINKYPTLKLFRNGmmmKR----EYRG 97

                        90
                ....*....|.
gi 94966757 137 PRDAEGIAEWL 147
Cdd:cd02996  98 QRSVEALAEFV 108

PDI family, MPD1-like subfamily; composed of eukaryotic proteins similar to Saccharomyces cerevisiae MPD1 protein, which contains a single redox active TRX domain located at the N-terminus, and an ER retention signal at the C-terminus indicative of an ER-resident protein. MPD1 has been shown to suppress the maturation defect of carboxypeptidase Y caused by deletion of the yeast PDI1 gene. Other characterized members of this subfamily include the Aspergillus niger prpA protein and Giardia PDI-1. PrpA is non-essential to strain viability, however, its transcript level is induced by heterologous protein expression suggesting a possible role in oxidative protein folding during high protein production. Giardia PDI-1 has the ability to refold scrambled RNase and exhibits transglutaminase activity.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 94966757 389 PVKTLVGKNFEQVAFDETKNVFVKFYAPWCTHCKEMAPAWEALAEkyQDHEDIIIAELDATAN---ELDA-FAVHGFPTL 464
Cdd:cd03002   1 PVYELTPKNFDKVVHNTNYTTLVEFYAPWCGHCKNLKPEYAKAAK--ELDGLVQVAAVDCDEDknkPLCGkYGVQGFPTL 78

                        90       100
                ....*....|....*....|....*....
gi 94966757 465 KYFPAGPG---RKVIEYKSTRDLETFSKF 490
Cdd:cd03002  79 KVFRPPKKaskHAVEDYNGERSAKAIVDF 107

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 94966757 396 KNFEQvAFDETKNVFVKFYAPWCTHCKEMAPAWEALAEKYqdhEDIIIAELDATANE--LDAFAVHGFPTLKYF 467
Cdd:cd02947   1 EEFEE-LIKSAKPVVVDFWAPWCGPCKAIAPVLEELAEEY---PKVKFVKVDVDENPelAEEYGVRSIPTFLFF 70

PDIa family, TMX subfamily; composed of proteins similar to the TRX-related human transmembrane protein, TMX. TMX is a type I integral membrane protein; the N-terminal redox active TRX domain is present in the endoplasmic reticulum (ER) lumen while the C-terminus is oriented towards the cytoplasm. It is expressed in many cell types and its active site motif (CPAC) is unique. In vitro, TMX reduces interchain disulfides of insulin and renatures inactive RNase containing incorrect disulfide bonds. The C. elegans homolog, DPY-11, is expressed only in the hypodermis and resides in the cytoplasm. It is required for body and sensory organ morphogeneis. Another uncharacterized TRX-related transmembrane protein, human TMX4, is included in the alignment. The active site sequence of TMX4 is CPSC.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 94966757 411 VKFYAPWCTHCKEMAPAWEALAEKYQDHEdIIIAELDATANE-LDA-FAVHGFPTLKYFPAGPGRKvieYKSTRDLETFS 488
Cdd:cd02994  21 IEFYAPWCPACQQLQPEWEEFADWSDDLG-INVAKVDVTQEPgLSGrFFVTALPTIYHAKDGVFRR---YQGPRDKEDLI 96

                ...
gi 94966757 489 KFL 491
Cdd:cd02994  97 SFI 99

PDIa family, 5'-Adenylylsulfate (APS) reductase subfamily; composed of plant-type APS reductases containing a C-terminal redox active TRX domain and an N-terminal reductase domain which is part of a superfamily that includes N type ATP PPases. APS reductase catalyzes the reduction of activated sulfate to sulfite, a key step in the biosynthesis of sulfur-containing metabolites. Sulfate is first activated by ATP sulfurylase, forming APS, which can be phosphorylated to 3'-phosphoadenosine-5'-phosphosulfate (PAPS). Depending on the organism, either APS or PAPS can be used for sulfate reduction. Prokaryotes and fungi use PAPS, whereas plants use both APS and PAPS. Since plant-type APS reductase uses glutathione (GSH) as its electron donor, the C-terminal domain may function like glutaredoxin, a GSH-dependent member of the TRX superfamily. The flow of reducing equivalents goes from GSH -> C-terminal TRX domain -> N-terminal reductase domain -> APS. Plant-type APS reductase shows no homology to that of dissimilatory sulfate-reducing bacteria, which is an iron-sulfur flavoenzyme. Also included in the alignment is EYE2 from Chlamydomonas reinhardtii, a protein required for eyespot assembly.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 94966757 407 KNVFVKFYAPWCTHCKEMAPAWEALAEKYQDHeDIIIAELDATAnELDAFA-----VHGFPTLKYFPAGpGRKVIEYKS- 480
Cdd:cd02993  22 QSTLVVLYAPWCPFCQAMEASYEELAEKLAGS-NVKVAKFNADG-EQREFAkeelqLKSFPTILFFPKN-SRQPIKYPSe 98

                        90
                ....*....|.
gi 94966757 481 TRDLETFSKFL 491
Cdd:cd02993  99 QRDVDSLLMFV 109