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 544186032  78 DVIELTPSNFNREVIQSDSLWLVEFYAPWCGHCQRLTPEWKKAATALKDVVKVGAVDADKHHSLGGQYGVQGFPTIKIFG 157
Cdd:cd03001    1 DVVELTDSNFDKKVLNSDDVWLVEFYAPWCGHCKNLAPEWKKAAKALKGIVKVGAVDADVHQSLAQQYGVRGFPTIKVFG 80

                         90       100
                 ....*....|....*....|...
gi 544186032 158 SNKNRPEDYQGGRTGEAIVDAAL 180
Cdd:cd03001   81 AGKNSPQDYQGGRTAKAIVSAAL 103

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 544186032  78 DVIELTPSNFNREVIQSDSLWLVEFYAPWCGHCQRLTPEWKKAATALKDVVKVGAVDADKHHSLGGQYGVQGFPTIKIFG 157
Cdd:cd03001    1 DVVELTDSNFDKKVLNSDDVWLVEFYAPWCGHCKNLAPEWKKAAKALKGIVKVGAVDADVHQSLAQQYGVRGFPTIKVFG 80

                         90       100
                 ....*....|....*....|...
gi 544186032 158 SNKNRPEDYQGGRTGEAIVDAAL 180
Cdd:cd03001   81 AGKNSPQDYQGGRTAKAIVSAAL 103

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 544186032  217 LTDDSFDKNVLDSEDVwMVEFYAPWCGHCKNLEPEWAAAASEVKEQtkGKVKLAAVDATVNQVLASRYGIRGFPTIKIFQ 296
Cdd:TIGR01126   1 LTASNFDEIVLSNKDV-LVEFYAPWCGHCKNLAPEYEKLAKELKKD--PKIVLAKVDATAEKDLASRFGVSGFPTIKFFP 77

                          90
                  ....*....|....*....
gi 544186032  297 KGESPVDYDGGRTRSDIVS 315
Cdd:TIGR01126  78 KGSKPVDYEGGRDLEAIVE 96

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 544186032   77 DDVIELTPSNFNrEVIQSDSLWLVEFYAPWCGHCQRLTPEWKKAATALKD---VVKVGAVDADKHHSLGGQYGVQGFPTI 153
Cdd:TIGR01130   1 EDVLVLTKDNFD-DFIKSHEFVLVEFYAPWCGHCKSLAPEYEKAADELKKkgpPIKLAKVDATEEKDLAQKYGVSGYPTL 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 544186032  154 KIFGSNKNRPEDYQGGRTGEAIVDaalsalrqLVKDrlggrsggyssgkqgRSDSSSKKdvIELTDDSfdKNVLDSEDVW 233
Cdd:TIGR01130  80 KIFRNGEDSVSDYNGPRDADGIVK--------YMKK---------------QSGPAVKE--IETVADL--EAFLADDDVV 132

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 544186032  234 MVEFYapwcghcKNLEPEWAAAASEVKEQTKGKVKLAAVDATVNqvLASRYGIrgFPTI------KIFQKGESPVDYDGG 307
Cdd:TIGR01130 133 VIGFF-------KDLDSELNDTFLSVAEKLRDVYFFFAHSSDVA--AFAKLGA--FPDSvvlfkpKDEDEKFSKVDGEMD 201

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 544186032  308 RTRSDIVsralDLFSDNAPPpeLLEIINEDIAKRTCEEHQLCVVAvlpHILDTGAAGRNSYLEVLLKLADKYKKKMWGWL 387
Cdd:TIGR01130 202 TDVSDLE----KFIRAESLP--LVGEFTQETAAKYFESGPLVVLY---YNVDESLDPFEELRNRFLEAAKKFRGKFVNFA 272

                         330       340       350       360       370
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 544186032  388 WT-EAGAQSELETaLGIGGFGYPAMAAINARKM-KFALLKGSFSEQGINEFLRELSFG 443
Cdd:TIGR01130 273 VAdEEDFGRELEY-FGLKAEKFPAVAIQDLEGNkKYPMDQEEFSSENLEAFVKDFLDG 329

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 544186032  214 VIELTDDSFDKNVLDSEDVWMVEFYAPWCGHCKNLEPEWAAAASEvkeqTKGKVKLAAVDATVNQVLASRYGIRGFPTIK 293
Cdd:pfam00085   2 VVVLTDANFDEVVQKSSKPVLVDFYAPWCGPCKMLAPEYEELAQE----YKGNVVFAKVDVDENPDLASKYGVRGYPTLI 77

                          90       100
                  ....*....|....*....|..
gi 544186032  294 IFQKGESPVDYDGGRTRSDIVS 315
Cdd:pfam00085  78 FFKNGQPVDDYVGARPKDALAA 99

disulphide isomerase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 544186032  76 SDDVIELTPSNFNReVIQSDSLWLVEFYAPWCGHCQRLTPEWKKAATALKDV---VKVGAVDADKHHSLGGQYGVQGFPT 152
Cdd:PTZ00102  31 SEHVTVLTDSTFDK-FITENEIVLVKFYAPWCGHCKRLAPEYKKAAKMLKEKkseIVLASVDATEEMELAQEFGVRGYPT 109

                         90       100
                 ....*....|....*....|....*
gi 544186032 153 IKIFgsNKNRPEDYQGGRTGEAIVD 177
Cdd:PTZ00102 110 IKFF--NKGNPVNYSGGRTADGIVS 132

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

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 544186032  79 VIELTPSNFNREVIQSDSLWLVEFYAPWCGHCQRLTPEWKKAATALKDVVKVGAVDADKHHSLGGQYGVQGFPTIKIF 156
Cdd:COG3118    2 VVELTDENFEEEVLESDKPVLVDFWAPWCGPCKMLAPVLEELAAEYGGKVKFVKVDVDENPELAAQFGVRSIPTLLLF 79

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 544186032  78 DVIELTPSNFNREVIQSDSLWLVEFYAPWCGHCQRLTPEWKKAATALKDVVKVGAVDADKHHSLGGQYGVQGFPTIKIFG 157
Cdd:cd03001    1 DVVELTDSNFDKKVLNSDDVWLVEFYAPWCGHCKNLAPEWKKAAKALKGIVKVGAVDADVHQSLAQQYGVRGFPTIKVFG 80

                         90       100
                 ....*....|....*....|...
gi 544186032 158 SNKNRPEDYQGGRTGEAIVDAAL 180
Cdd:cd03001   81 AGKNSPQDYQGGRTAKAIVSAAL 103

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 544186032  217 LTDDSFDKNVLDSEDVwMVEFYAPWCGHCKNLEPEWAAAASEVKEQtkGKVKLAAVDATVNQVLASRYGIRGFPTIKIFQ 296
Cdd:TIGR01126   1 LTASNFDEIVLSNKDV-LVEFYAPWCGHCKNLAPEYEKLAKELKKD--PKIVLAKVDATAEKDLASRFGVSGFPTIKFFP 77

                          90
                  ....*....|....*....
gi 544186032  297 KGESPVDYDGGRTRSDIVS 315
Cdd:TIGR01126  78 KGSKPVDYEGGRDLEAIVE 96

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 544186032 215 IELTDDSFDKNVLDSEDvWMVEFYAPWCGHCKNLEPEWAAAASEVKEqtKGKVKLAAVDATVNQVLASRYGIRGFPTIKI 294
Cdd:cd02961    1 VELTDDNFDELVKDSKD-VLVEFYAPWCGHCKALAPEYEKLAKELKG--DGKVVVAKVDCTANNDLCSEYGVRGYPTIKL 77

                         90       100
                 ....*....|....*....|..
gi 544186032 295 FQKGES-PVDYDGGRTRSDIVS 315
Cdd:cd02961   78 FPNGSKePVKYEGPRTLESLVE 99

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 544186032  79 VIELTPSNFNREVIQSDSLWLVEFYAPWCGHCQRLTPEWKKAATALKDVVKVGAV--DADKHHSLGGQYGVQGFPTIKIF 156
Cdd:cd03002    2 VYELTPKNFDKVVHNTNYTTLVEFYAPWCGHCKNLKPEYAKAAKELDGLVQVAAVdcDEDKNKPLCGKYGVQGFPTLKVF 81

                         90       100
                 ....*....|....*....|....*...
gi 544186032 157 ----GSNKNRPEDYQGGRTGEAIVDAAL 180
Cdd:cd03002   82 rppkKASKHAVEDYNGERSAKAIVDFVL 109

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 544186032   77 DDVIELTPSNFNrEVIQSDSLWLVEFYAPWCGHCQRLTPEWKKAATALKD---VVKVGAVDADKHHSLGGQYGVQGFPTI 153
Cdd:TIGR01130   1 EDVLVLTKDNFD-DFIKSHEFVLVEFYAPWCGHCKSLAPEYEKAADELKKkgpPIKLAKVDATEEKDLAQKYGVSGYPTL 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 544186032  154 KIFGSNKNRPEDYQGGRTGEAIVDaalsalrqLVKDrlggrsggyssgkqgRSDSSSKKdvIELTDDSfdKNVLDSEDVW 233
Cdd:TIGR01130  80 KIFRNGEDSVSDYNGPRDADGIVK--------YMKK---------------QSGPAVKE--IETVADL--EAFLADDDVV 132

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 544186032  234 MVEFYapwcghcKNLEPEWAAAASEVKEQTKGKVKLAAVDATVNqvLASRYGIrgFPTI------KIFQKGESPVDYDGG 307
Cdd:TIGR01130 133 VIGFF-------KDLDSELNDTFLSVAEKLRDVYFFFAHSSDVA--AFAKLGA--FPDSvvlfkpKDEDEKFSKVDGEMD 201

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 544186032  308 RTRSDIVsralDLFSDNAPPpeLLEIINEDIAKRTCEEHQLCVVAvlpHILDTGAAGRNSYLEVLLKLADKYKKKMWGWL 387
Cdd:TIGR01130 202 TDVSDLE----KFIRAESLP--LVGEFTQETAAKYFESGPLVVLY---YNVDESLDPFEELRNRFLEAAKKFRGKFVNFA 272

                         330       340       350       360       370
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 544186032  388 WT-EAGAQSELETaLGIGGFGYPAMAAINARKM-KFALLKGSFSEQGINEFLRELSFG 443
Cdd:TIGR01130 273 VAdEEDFGRELEY-FGLKAEKFPAVAIQDLEGNkKYPMDQEEFSSENLEAFVKDFLDG 329

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 544186032  78 DVIELTPSNFNREVIQSDSLWLVEFYAPWCGHCQRLTPEWKKAATALK--DVVKVGAVDADK-HHSLGGQYGVQGFPTIK 154
Cdd:cd02998    1 NVVELTDSNFDKVVGDDKKDVLVEFYAPWCGHCKNLAPEYEKLAAVFAneDDVVIAKVDADEaNKDLAKKYGVSGFPTLK 80

                         90       100
                 ....*....|....*....|..
gi 544186032 155 IFGSNKNRPEDYQGGRTGEAIV 176
Cdd:cd02998   81 FFPKGSTEPVKYEGGRDLEDLV 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 544186032  214 VIELTDDSFDKNVLDSEDVWMVEFYAPWCGHCKNLEPEWAAAASEvkeqTKGKVKLAAVDATVNQVLASRYGIRGFPTIK 293
Cdd:pfam00085   2 VVVLTDANFDEVVQKSSKPVLVDFYAPWCGPCKMLAPEYEELAQE----YKGNVVFAKVDVDENPDLASKYGVRGYPTLI 77

                          90       100
                  ....*....|....*....|..
gi 544186032  294 IFQKGESPVDYDGGRTRSDIVS 315
Cdd:pfam00085  78 FFKNGQPVDDYVGARPKDALAA 99

disulphide isomerase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 544186032 213 DVIELTDDSFDKNVLDSEDVwMVEFYAPWCGHCKNLEPEWAAAASEVKEQtKGKVKLAAVDATVNQVLASRYGIRGFPTI 292
Cdd:PTZ00102  33 HVTVLTDSTFDKFITENEIV-LVKFYAPWCGHCKRLAPEYKKAAKMLKEK-KSEIVLASVDATEEMELAQEFGVRGYPTI 110

                         90       100
                 ....*....|....*....|....*...
gi 544186032 293 KIFQKGEsPVDYDGGRTRSDIVSRALDL 320
Cdd:PTZ00102 111 KFFNKGN-PVNYSGGRTADGIVSWIKKL 137

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 544186032 214 VIELTDDSFDKNVLDSEDVWMVEFYAPWCGHCKNLEPEWAAAASEVkeqtKGKVKLAAV--DATVNQVLASRYGIRGFPT 291
Cdd:cd03002    2 VYELTPKNFDKVVHNTNYTTLVEFYAPWCGHCKNLKPEYAKAAKEL----DGLVQVAAVdcDEDKNKPLCGKYGVQGFPT 77

                         90       100       110
                 ....*....|....*....|....*....|..
gi 544186032 292 IKIFQKGE-----SPVDYDGGRTRSDIVSRAL 318
Cdd:cd03002   78 LKVFRPPKkaskhAVEDYNGERSAKAIVDFVL 109

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 544186032 214 VIELtDDSFDKNvlDSEDVWMVEFYAPWCGHCKNLEPEWAAAASEVKEqTKGKVKLAAVDATVNQVLASRYGIRGFPTIK 293
Cdd:cd03000    2 VLDL-DDSFKDV--RKEDIWLVDFYAPWCGHCKKLEPVWNEVGAELKS-SGSPVRVGKLDATAYSSIASEFGVRGYPTIK 77

                         90       100
                 ....*....|....*....|....*
gi 544186032 294 IFqKGESPVDYDGGRTRSDIVSRAL 318
Cdd:cd03000   78 LL-KGDLAYNYRGPRTKDDIVEFAN 101

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 544186032 214 VIELTDDSFDKNVLDSE-DVwMVEFYAPWCGHCKNLEPEWAAAASEVKeqTKGKVKLAAVDATVNQVLASrYGIRGFPTI 292
Cdd:cd02995    2 VKVVVGKNFDEVVLDSDkDV-LVEFYAPWCGHCKALAPIYEELAEKLK--GDDNVVIAKMDATANDVPSE-FVVDGFPTI 77

                         90       100
                 ....*....|....*....|....
gi 544186032 293 KIFQKG--ESPVDYDGGRTRSDIV 314
Cdd:cd02995   78 LFFPAGdkSNPIKYEGDRTLEDLI 101

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 544186032 214 VIELTDDSFDKNVLDSEDVWMVEFYAPWCGHCKNLEPEWAAAASevkeQTKGKVKLAAVDATVNQVLASRYGIRGFPTIK 293
Cdd:cd03004    3 VITLTPEDFPELVLNRKEPWLVDFYAPWCGPCQALLPELRKAAR----ALKGKVKVGSVDCQKYESLCQQANIRAYPTIR 78

                         90
                 ....*....|....
gi 544186032 294 IFQKGESPV-DYDG 306
Cdd:cd03004   79 LYPGNASKYhSYNG 92

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 544186032  78 DVIELTPSNFnREVIQSDSLWLVEFYAPWCGHCQRLTPEWKKAATALKDVVKV--GAVDADK--HHSLGGQYGVQGFPTI 153
Cdd:cd02997    1 DVVHLTDEDF-RKFLKKEKHVLVMFYAPWCGHCKKMKPEFTKAATELKEDGKGvlAAVDCTKpeHDALKEEYNVKGFPTF 79

                         90       100
                 ....*....|....*....|....
gi 544186032 154 KIFgSNKNRPEDYQGGRTGEAIVD 177
Cdd:cd02997   80 KYF-ENGKFVEKYEGERTAEDIIE 102

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 544186032  95 DSLWLVEFYAPWCGHCQRLTPEWKKAATALKDV---VKVGAVDADKHHSLGGQYGVQGFPTIKIFgsNKNRPEDYQGGRT 171
Cdd:cd03000   15 EDIWLVDFYAPWCGHCKKLEPVWNEVGAELKSSgspVRVGKLDATAYSSIASEFGVRGYPTIKLL--KGDLAYNYRGPRT 92

                 ....*....
gi 544186032 172 GEAIVDAAL 180
Cdd:cd03000   93 KDDIVEFAN 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 544186032  79 VIELTPSNFNREVIQSDSLwlVEFYAPWCGHCQRLTPEWKKAATALKDV---VKVGAVDADKHHSLGGQYGVQGFPTIKI 155
Cdd:cd03005    2 VLELTEDNFDHHIAEGNHF--VKFFAPWCGHCKRLAPTWEQLAKKFNNEnpsVKIAKVDCTQHRELCSEFQVRGYPTLLL 79

                         90       100
                 ....*....|....*....|
gi 544186032 156 FGSNKnRPEDYQGGRTGEAI 175
Cdd:cd03005   80 FKDGE-KVDKYKGTRDLDSL 98

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 544186032   74 SSSDDVIELTPSNFNREVIQSDSLWLVEFYAPWCGHCQRLTPEWKKAATALKDV---VKVGAVDADKHHSLGgqYGVQGF 150
Cdd:TIGR01130 343 DDEGPVKVLVGKNFDEIVLDETKDVLVEFYAPWCGHCKNLAPIYEELAEKYKDAesdVVIAKMDATANDVPP--FEVEGF 420

                          90       100
                  ....*....|....*....|....*...
gi 544186032  151 PTIKIF-GSNKNRPEDYQGGRTGEAIVD 177
Cdd:TIGR01130 421 PTIKFVpAGKKSEPVPYDGDRTLEDFSK 448

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 544186032 214 VIELTDDSFDKNVLDSEDVWMVEFYAPWCGHCKNLEPEWAAAASEVKEQtKGKVKLAAVD--ATVNQVLASRYGIRGFPT 291
Cdd:cd02992    3 VIVLDAASFNSALLGSPSAWLVEFYASWCGHCRAFAPTWKKLARDLRKW-RPVVRVAAVDcaDEENVALCRDFGVTGYPT 81

                 ....
gi 544186032 292 IKIF 295
Cdd:cd02992   82 LRYF 85