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 575771837  82 GLYELSANNFELHVSQGNHFIKFFAPWCGHCKALAPTWEQLALGLEH-SETVKIGKVDCTQHYAVCSEHQVRGYPTLLWF 160
Cdd:cd03005    1 GVLELTEDNFDHHIAEGNHFVKFFAPWCGHCKRLAPTWEQLAKKFNNeNPSVKIAKVDCTQHRELCSEFQVRGYPTLLLF 80

                         90       100
                 ....*....|....*....|..
gi 575771837 161 RDGKKVDQYKGKRDLESLRDYV 182
Cdd:cd03005   81 KDGEKVDKYKGTRDLDSLKEFV 102

Protein Disulfide Oxidoreductases and Other Proteins with a Thioredoxin fold; The thioredoxin (TRX)-like superfamily is a large, diverse group of proteins containing a TRX fold. Many members contain a classic TRX domain with a redox active CXXC motif. They function as protein disulfide oxidoreductases (PDOs), altering the redox state of target proteins via the reversible oxidation of their active site dithiol. The PDO members of this superfamily include the families of TRX, protein disulfide isomerase (PDI), tlpA, glutaredoxin, NrdH redoxin, and bacterial Dsb proteins (DsbA, DsbC, DsbG, DsbE, DsbDgamma). Members of the superfamily that do not function as PDOs but contain a TRX-fold domain include phosducins, peroxiredoxins, glutathione (GSH) peroxidases, SCO proteins, GSH transferases (GST, N-terminal domain), arsenic reductases, TRX-like ferredoxins and calsequestrin, among others.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 575771837   2 EDAKVYVAKVDCTADSDVCSAQGVRGYPTLKFFKPGQEAVKYQGPRDFETLENWM 56
Cdd:cd03005   48 ENPSVKIAKVDCTQHRELCSEFQVRGYPTLLLFKDGEKVDKYKGTRDLDSLKEFV 102

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 575771837  82 GLYELSANNFELHVSQGNHFIKFFAPWCGHCKALAPTWEQLALGLEH-SETVKIGKVDCTQHYAVCSEHQVRGYPTLLWF 160
Cdd:cd03005    1 GVLELTEDNFDHHIAEGNHFVKFFAPWCGHCKRLAPTWEQLAKKFNNeNPSVKIAKVDCTQHRELCSEFQVRGYPTLLLF 80

                         90       100
                 ....*....|....*....|..
gi 575771837 161 RDGKKVDQYKGKRDLESLRDYV 182
Cdd:cd03005   81 KDGEKVDKYKGTRDLDSLKEFV 102

protein disulfide-isomerase domain; This model describes a domain of eukaryotic protein disulfide isomerases, generally found in two copies. The high cutoff for total score reflects the expectation of finding both copies. The domain is similar to thioredoxin but the redox-active disulfide region motif is APWCGHCK. [Protein fate, Protein folding and stabilization]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 575771837  218 LTEKSFEDTIAQG-ITFVKFYAPWCGHCKNLAPTWEELSkKEFPGLSDVTIAEVDCTAERNVCSKYSVRGYPTLLLFRGG 296
Cdd:TIGR01126   1 LTASNFDEIVLSNkDVLVEFYAPWCGHCKNLAPEYEKLA-KELKKDPKIVLAKVDATAEKDLASRFGVSGFPTIKFFPKG 79

                          90       100
                  ....*....|....*....|...
gi 575771837  297 EKVGEHNGGRDLDSLHSFVLRQA 319
Cdd:TIGR01126  80 SKPVDYEGGRDLEAIVEFVNEKS 102

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 575771837  215 VLALTEKSFEDTIAQGITF--VKFYAPWCGHCKNLAPTWEELSKkEFPGlsDVTIAEVDCTAERNVCSKYSVRGYPTLLL 292
Cdd:pfam00085   2 VVVLTDANFDEVVQKSSKPvlVDFYAPWCGPCKMLAPEYEELAQ-EYKG--NVVFAKVDVDENPDLASKYGVRGYPTLIF 78

                          90       100
                  ....*....|....*....|...
gi 575771837  293 FRGGEKVGEHNGGRDLDSLHSFV 315
Cdd:pfam00085  79 FKNGQPVDDYVGARPKDALAAFL 101

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
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 575771837   2 EDAKVYVAKVDCTADSDVCSAQGVRGYPTLKFFKPGQEAVKYQGPRDFETLENWM 56
Cdd:cd03005   48 ENPSVKIAKVDCTQHRELCSEFQVRGYPTLLLFKDGEKVDKYKGTRDLDSLKEFV 102

disulphide isomerase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 575771837 215 VLALTEKSFEDTIAQG-ITFVKFYAPWCGHCKNLAPTWEELSKKEFPGLSDVTIAEVDCTAERNVCSKYSVRGYPTLLLF 293
Cdd:PTZ00102  34 VTVLTDSTFDKFITENeIVLVKFYAPWCGHCKRLAPEYKKAAKMLKEKKSEIVLASVDATEEMELAQEFGVRGYPTIKFF 113

                         90       100
                 ....*....|....*....|..
gi 575771837 294 RGGEKVgEHNGGRDLDSLHSFV 315
Cdd:PTZ00102 114 NKGNPV-NYSGGRTADGIVSWI 134

disulphide isomerase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 575771837  85 ELSANNFELHVSQGNH-FIKFFAPWCGHCKALAPTWEQLALGL-EHSETVKIGKVDCTQHYAVCSEHQVRGYPTLLWFRD 162
Cdd:PTZ00102  36 VLTDSTFDKFITENEIvLVKFYAPWCGHCKRLAPEYKKAAKMLkEKKSEIVLASVDATEEMELAQEFGVRGYPTIKFFNK 115

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 575771837 163 GKKVDqYKGKRDLESLRDYVQsQLQGSeAAPETVEPSEAPVMAAE 207
Cdd:PTZ00102 116 GNPVN-YSGGRTADGIVSWIK-KLTGP-AVTEVESASEIKLIAKK 157

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

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 575771837   5 KVYVAKVDCTADSDVCSAQGVRGYPTLKFFKPGQEAVKYQGPRDFETLENWM 56
Cdd:COG3118   50 KVKFVKVDVDENPELAAQFGVRSIPTLLLFKDGQPVDRFVGALPKEQLREFL 101

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 575771837  82 GLYELSANNFELHVSQGNHFIKFFAPWCGHCKALAPTWEQLALGLEH-SETVKIGKVDCTQHYAVCSEHQVRGYPTLLWF 160
Cdd:cd03005    1 GVLELTEDNFDHHIAEGNHFVKFFAPWCGHCKRLAPTWEQLAKKFNNeNPSVKIAKVDCTQHRELCSEFQVRGYPTLLLF 80

                         90       100
                 ....*....|....*....|..
gi 575771837 161 RDGKKVDQYKGKRDLESLRDYV 182
Cdd:cd03005   81 KDGEKVDKYKGTRDLDSLKEFV 102

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 575771837  85 ELSANNFELHVSQGNH-FIKFFAPWCGHCKALAPTWEQLALGLEHSETVKIGKVDCTQHYAVCSEHQVRGYPTLLWFRDG 163
Cdd:cd02961    2 ELTDDNFDELVKDSKDvLVEFYAPWCGHCKALAPEYEKLAKELKGDGKVVVAKVDCTANNDLCSEYGVRGYPTIKLFPNG 81

                         90       100
                 ....*....|....*....|
gi 575771837 164 -KKVDQYKGKRDLESLRDYV 182
Cdd:cd02961   82 sKEPVKYEGPRTLESLVEFI 101

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 575771837 218 LTEKSFEDTIAQG-ITFVKFYAPWCGHCKNLAPTWEELSKKeFPGLSDVTIAEVDCTAERNVCSKYSVRGYPTLLLFRGG 296
Cdd:cd02961    3 LTDDNFDELVKDSkDVLVEFYAPWCGHCKALAPEYEKLAKE-LKGDGKVVVAKVDCTANNDLCSEYGVRGYPTIKLFPNG 81

                         90       100
                 ....*....|....*....|
gi 575771837 297 -EKVGEHNGGRDLDSLHSFV 315
Cdd:cd02961   82 sKEPVKYEGPRTLESLVEFI 101

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 575771837   85 ELSANNFELHVSQGNHFI-KFFAPWCGHCKALAPTWEQLALGL-EHSETVKIGKVDCTQHYAVCSEHQVRGYPTLLWFRD 162
Cdd:TIGR01130   5 VLTKDNFDDFIKSHEFVLvEFYAPWCGHCKSLAPEYEKAADELkKKGPPIKLAKVDATEEKDLAQKYGVSGYPTLKIFRN 84

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 575771837  163 GKKVDQ----------------------------------YKGKRDL---------------------ESLRDYVQSQLQ 187
Cdd:TIGR01130  85 GEDSVSdyngprdadgivkymkkqsgpavkeietvadleaFLADDDVvvigffkdldselndtflsvaEKLRDVYFFFAH 164

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 575771837  188 GS------------------------------------------------------------------------------ 189
Cdd:TIGR01130 165 SSdvaafaklgafpdsvvlfkpkdedekfskvdgemdtdvsdlekfiraeslplvgeftqetaakyfesgplvvlyynvd 244

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 575771837  190 --------------EAAPE---------------------------------------------------TVEPSEA--- 201
Cdd:TIGR01130 245 esldpfeelrnrflEAAKKfrgkfvnfavadeedfgreleyfglkaekfpavaiqdlegnkkypmdqeefSSENLEAfvk 324

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 575771837  202 --------PVMAAE--PTGDKGTVLALTEKSFEDTI--AQGITFVKFYAPWCGHCKNLAPTWEELSKKEFPGLSDVTIAE 269
Cdd:TIGR01130 325 dfldgklkPYLKSEpiPEDDEGPVKVLVGKNFDEIVldETKDVLVEFYAPWCGHCKNLAPIYEELAEKYKDAESDVVIAK 404

                         410       420       430       440       450
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 575771837  270 VDCTAerNVCSKYSVRGYPTLLLFRGGEKVG--EHNGGRDLDSLHSFVLRQAKDEL 323
Cdd:TIGR01130 405 MDATA--NDVPPFEVEGFPTIKFVPAGKKSEpvPYDGDRTLEDFSKFIAKHATFPL 458

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 575771837  215 VLALTEKSFEDTIAQG-ITFVKFYAPWCGHCKNLAPTWE----ELSKKEfpglSDVTIAEVDCTAERNVCSKYSVRGYPT 289
Cdd:TIGR01130   3 VLVLTKDNFDDFIKSHeFVLVEFYAPWCGHCKSLAPEYEkaadELKKKG----PPIKLAKVDATEEKDLAQKYGVSGYPT 78

                          90       100       110
                  ....*....|....*....|....*....|.
gi 575771837  290 LLLFRGGEK-VGEHNGGRDLDSLHSFVLRQA 319
Cdd:TIGR01130  79 LKIFRNGEDsVSDYNGPRDADGIVKYMKKQS 109

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 575771837  85 ELSANNFELHV--SQGNHFIKFFAPWCGHCKALAPTWEQLALGLEHSETVKIGKVDCTQ-HYAVCSEHQVRGYPTLLWF- 160
Cdd:cd02998    4 ELTDSNFDKVVgdDKKDVLVEFYAPWCGHCKNLAPEYEKLAAVFANEDDVVIAKVDADEaNKDLAKKYGVSGFPTLKFFp 83

                         90       100
                 ....*....|....*....|..
gi 575771837 161 RDGKKVDQYKGKRDLESLRDYV 182
Cdd:cd02998   84 KGSTEPVKYEGGRDLEDLVKFV 105

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
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 575771837   2 EDAKVYVAKVDCTADSDVCSAQGVRGYPTLKFFKPGQEAVKYQGPRDFETLENWM 56
Cdd:cd03005   48 ENPSVKIAKVDCTQHRELCSEFQVRGYPTLLLFKDGEKVDKYKGTRDLDSLKEFV 102

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 575771837 215 VLALTEKSFEDTIAQG--ITFVKFYAPWCGHCKNLAPTWEELSkKEFPGLSDVtiAEVDCTAERN--VCSKYSVRGYPTL 290
Cdd:cd03002    2 VYELTPKNFDKVVHNTnyTTLVEFYAPWCGHCKNLKPEYAKAA-KELDGLVQV--AAVDCDEDKNkpLCGKYGVQGFPTL 78

                         90       100       110
                 ....*....|....*....|....*....|.
gi 575771837 291 LLFRGGEKVGEH-----NGGRDLDSLHSFVL 316
Cdd:cd03002   79 KVFRPPKKASKHavedyNGERSAKAIVDFVL 109

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 575771837 214 TVLALTEKSFEDTI--AQGITFVKFYAPWCGHCKNLAPTWEELSKkEFPGlsDVTIAEVDCTAERNVCSKYSVRGYPTLL 291
Cdd:COG3118    1 AVVELTDENFEEEVleSDKPVLVDFWAPWCGPCKMLAPVLEELAA-EYGG--KVKFVKVDVDENPELAAQFGVRSIPTLL 77

                         90       100
                 ....*....|....*....|....
gi 575771837 292 LFRGGEKVGEHNGGRDLDSLHSFV 315
Cdd:COG3118   78 LFKDGQPVDRFVGALPKEQLREFL 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 575771837  85 ELSANNFELHVSQGNH--FIKFFAPWCGHCKALAPTWEQLALGLEhsETVKIGKVDCTQHYAVCSEHQVRGYPTLLWFRD 162
Cdd:cd03001    4 ELTDSNFDKKVLNSDDvwLVEFYAPWCGHCKNLAPEWKKAAKALK--GIVKVGAVDADVHQSLAQQYGVRGFPTIKVFGA 81

                         90
                 ....*....|....*....
gi 575771837 163 GKKVDQ-YKGKRDLESLRD 180
Cdd:cd03001   82 GKNSPQdYQGGRTAKAIVS 100

Thioredoxin domain-containing protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 575771837 211 DKGTVLALTEKSFEDTI------AQGITFVKFYAPWCGHCKNLAPTWEELSkKEFPGLsdVTIAEVDCTAERNVCSKYSV 284
Cdd:PTZ00443  28 DANALVLLNDKNFEKLTqastgaTTGPWFVKFYAPWCSHCRKMAPAWERLA-KALKGQ--VNVADLDATRALNLAKRFAI 104

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 575771837 285 RGYPTLLLFRGGEKVGEHNGGRDLDSLHSFVLRQAKDEL 323
Cdd:PTZ00443 105 KGYPTLLLFDKGKMYQYEGGDRSTEKLAAFALGDFKKAL 143

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 575771837  85 ELSANNFELHVSQGNH--FIKFFAPWCGHCKALAPTWEQLALglEHSETVKIGKVDCTQHYAVCSEHQVRGYPTLLWFRD 162
Cdd:COG3118    4 ELTDENFEEEVLESDKpvLVDFWAPWCGPCKMLAPVLEELAA--EYGGKVKFVKVDVDENPELAAQFGVRSIPTLLLFKD 81

                         90       100
                 ....*....|....*....|....
gi 575771837 163 GKKVDQYKGKRDLESLRDYVQSQL 186
Cdd:COG3118   82 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 575771837   30 TLKFFKPGQEAvkyqgprDFETLENWMLQTLNEEpATPEPEAEPprAPELKQG-LYELSANNFELHV--SQGNHFIKFFA 106
Cdd:TIGR01130 304 NKKYPMDQEEF-------SSENLEAFVKDFLDGK-LKPYLKSEP--IPEDDEGpVKVLVGKNFDEIVldETKDVLVEFYA 373

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 575771837  107 PWCGHCKALAPTWEQLALGLEHSET-VKIGKVDCTQHYAvcSEHQVRGYPTLLWFRDGKKVD--QYKGKRDLESLRDYV 182
Cdd:TIGR01130 374 PWCGHCKNLAPIYEELAEKYKDAESdVVIAKMDATANDV--PPFEVEGFPTIKFVPAGKKSEpvPYDGDRTLEDFSKFI 450

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 575771837 221 KSFEDTIAQ-GITFVKFYAPWCGHCKNLAPTWEELSKKEfpglSDVTIAEVDCTAERNVCSKYSVRGYPTLLLFRGGEKV 299
Cdd:cd02947    1 EEFEELIKSaKPVVVDFWAPWCGPCKAIAPVLEELAEEY----PKVKFVKVDVDENPELAEEYGVRSIPTFLFFKNGKEV 76

                         90
                 ....*....|....*.
gi 575771837 300 GEHNGGRDLDSLHSFV 315
Cdd:cd02947   77 DRVVGADPKEELEEFL 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 575771837 101 FIKFFAPWCGHCKALAPTWEQLALGLEHSET-VKIGKVDCTQHYAVCSEHQVRGYPTLLWFRDGKKVDqYKGKRDLESLR 179
Cdd:cd03000   19 LVDFYAPWCGHCKKLEPVWNEVGAELKSSGSpVRVGKLDATAYSSIASEFGVRGYPTIKLLKGDLAYN-YRGPRTKDDIV 97

                 ..
gi 575771837 180 DY 181
Cdd:cd03000   98 EF 99

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 575771837 215 VLALTEKSFEDTI--AQGITFVKFYAPWCGHCKNLAPTWEELSK--KEFPGLsdVTIAEVDCTAERN--VCSKYSVRGYP 288
Cdd:cd02992    3 VIVLDAASFNSALlgSPSAWLVEFYASWCGHCRAFAPTWKKLARdlRKWRPV--VRVAAVDCADEENvaLCRDFGVTGYP 80

                 ....*.
gi 575771837 289 TLLLFR 294
Cdd:cd02992   81 TLRYFP 86

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 575771837  90 NFELHVSQ-GNHFIKFFAPWCGHCKALAPTWEQLAlglEHSETVKIGKVDCTQHYAVCSEHQVRGYPTLLWFRDGKKVDQ 168
Cdd:cd02947    2 EFEELIKSaKPVVVDFWAPWCGPCKAIAPVLEELA---EEYPKVKFVKVDVDENPELAEEYGVRSIPTFLFFKNGKEVDR 78

                         90
                 ....*....|....*
gi 575771837 169 YKGKRDLESLRDYVQ 183
Cdd:cd02947   79 VVGADPKEELEEFLE 93

PDIa family, C-terminal ERdj5 subfamily; ERdj5, also known as JPDI and macrothioredoxin, is a protein containing an N-terminal DnaJ domain and four redox active TRX domains. This subfamily is composed of the three TRX domains located at the C-terminal half of the protein. ERdj5 is a ubiquitous protein localized in the endoplasmic reticulum (ER) and is abundant in secretory cells. It's transcription is induced during ER stress. It interacts with BiP through its DnaJ domain in an ATP-dependent manner. BiP, an ER-resident member of the Hsp70 chaperone family, functions in ER-associated degradation and protein translocation. Also included in the alignment is the single complete TRX domain of an uncharacterized protein from Tetraodon nigroviridis, which also contains a DnaJ domain at its N-terminus.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 575771837 215 VLALTEKSFEDTIAQG--ITFVKFYAPWCGHCKNLAPTWEELSKKEFPglsDVTIAEVDCTAERNVCSKYSVRGYPTLLL 292
Cdd:cd03004    3 VITLTPEDFPELVLNRkePWLVDFYAPWCGPCQALLPELRKAARALKG---KVKVGSVDCQKYESLCQQANIRAYPTIRL 79

                         90       100
                 ....*....|....*....|....*
gi 575771837 293 FRGGE-KVGEHNG-GRDLDSLHSFV 315
Cdd:cd03004   80 YPGNAsKYHSYNGwHRDADSILEFI 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 575771837 213 GTVLALTEKSFEDTI-AQGITFVKFYAPWCGHCKNLAPTWEELS---KKEFPGLSDVTIAEVDCTAERNVCSKYSVRGYP 288
Cdd:cd02996    1 SEIVSLTSGNIDDILqSAELVLVNFYADWCRFSQMLHPIFEEAAakiKEEFPDAGKVVWGKVDCDKESDIADRYRINKYP 80

                         90       100
                 ....*....|....*....|....*...
gi 575771837 289 TLLLFRGGEKVG-EHNGGRDLDSLHSFV 315
Cdd:cd02996   81 TLKLFRNGMMMKrEYRGQRSVEALAEFV 108

PDIa family, N-terminal ERdj5 subfamily; ERdj5, also known as JPDI and macrothioredoxin, is a protein containing an N-terminal DnaJ domain and four redox active TRX domains. This subfamily is comprised of the first TRX domain of ERdj5 located after the DnaJ domain at the N-terminal half of the protein. ERdj5 is a ubiquitous protein localized in the endoplasmic reticulum (ER) and is abundant in secretory cells. It's transcription is induced during ER stress. It interacts with BiP through its DnaJ domain in an ATP-dependent manner. BiP, an ER-resident member of the Hsp70 chaperone family, functions in ER-associated degradation and protein translocation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 575771837  86 LSANNFELHVSQGN-HFIKFFAPWCGHCKALAPTWEQLALGLEHseTVKIGKVDCTQHYAVCSEHQVRGYPTLLWFRDGK 164
Cdd:cd03003    6 LDRGDFDAAVNSGEiWFVNFYSPRCSHCHDLAPTWREFAKEMDG--VIRIGAVNCGDDRMLCRSQGVNSYPSLYVFPSGM 83

                         90
                 ....*....|....*..
gi 575771837 165 KVDQYKGKRDLESLRDY 181
Cdd:cd03003   84 NPEKYYGDRSKESLVKF 100

PDIa family, PDIR subfamily; composed of proteins similar to human PDIR (for Protein Disulfide Isomerase Related). PDIR is composed of three redox active TRX (a) domains and an N-terminal redox inactive TRX-like (b) domain. Similar to PDI, it is involved in oxidative protein folding in the endoplasmic reticulum (ER) through its isomerase and chaperone activities. These activities are lower compared to PDI, probably due to PDIR acting only on a subset of proteins. PDIR is preferentially expressed in cells actively secreting proteins and its expression is induced by stress. Similar to PDI, the isomerase and chaperone activities of PDIR are independent; CXXC mutants lacking isomerase activity retain chaperone activity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 575771837 215 VLALTEKSFEDTIAQGI-TFVKFYAPWCGHCKNLAPTWEELSkKEFPGLSDVTIAEVDCTAERN--VCSKYSVRGYPTLL 291
Cdd:cd02997    2 VVHLTDEDFRKFLKKEKhVLVMFYAPWCGHCKKMKPEFTKAA-TELKEDGKGVLAAVDCTKPEHdaLKEEYNVKGFPTFK 80