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 163776139 142 HVKVLDPTNFDAIALDTDKDVLVEFYAPWCGHCKSVAPIYEKAGLAFANEENVVVAKVDADK-HSELASKFGVSGFPTFK 220
Cdd:cd02998    1 NVVELTDSNFDKVVGDDKKDVLVEFYAPWCGHCKNLAPEYEKLAAVFANEDDVVIAKVDADEaNKDLAKKYGVSGFPTLK 80

                         90       100
                 ....*....|....*....|....*
gi 163776139 221 FFPKGSTEAEDYSSGRELQSFLTFL 245
Cdd:cd02998   81 FFPKGSTEPVKYEGGRDLEDLVKFV 105

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 163776139  24 DVIDLTPDTFDDIINGDR-PALVEFFAPWCGHCKSLAPTWEELGTAYASQKDVIIAKVDASE-HRDLGSRFGVTGFPTLK 101
Cdd:cd02998    1 NVVELTDSNFDKVVGDDKkDVLVEFYAPWCGHCKNLAPEYEKLAAVFANEDDVVIAKVDADEaNKDLAKKYGVSGFPTLK 80

                         90       100
                 ....*....|....*....|....
gi 163776139 102 FFPKGSTEPEDYKGGRALNDLADF 125
Cdd:cd02998   81 FFPKGSTEPVKYEGGRDLEDLVKF 104

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 163776139  146 LDPTNFDAIALDtDKDVLVEFYAPWCGHCKSVAPIYEKAGLAFANEENVVVAKVDADKHSELASKFGVSGFPTFKFFPKG 225
Cdd:TIGR01126   1 LTASNFDEIVLS-NKDVLVEFYAPWCGHCKNLAPEYEKLAKELKKDPKIVLAKVDATAEKDLASRFGVSGFPTIKFFPKG 79

                          90       100
                  ....*....|....*....|....
gi 163776139  226 STeAEDYSSGRELQSFLTFLNEKA 249
Cdd:TIGR01126  80 SK-PVDYEGGRDLEAIVEFVNEKS 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 163776139   25 VIDLTPDTFDDII-NGDRPALVEFFAPWCGHCKSLAPTWEELGTAYAsqKDVIIAKVDASEHRDLGSRFGVTGFPTLKFF 103
Cdd:pfam00085   2 VVVLTDANFDEVVqKSSKPVLVDFYAPWCGPCKMLAPEYEELAQEYK--GNVVFAKVDVDENPDLASKYGVRGYPTLIFF 79

                          90       100
                  ....*....|....*....|...
gi 163776139  104 PKGStEPEDYKGGRALNDLADFM 126
Cdd:pfam00085  80 KNGQ-PVDDYVGARPKDALAAFL 101

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 163776139 142 HVKVLDPTNFDAIALDTDKDVLVEFYAPWCGHCKSVAPIYEKagLAFANEENVVVAKVDADKHSELASKFGVSGFPTFKF 221
Cdd:COG3118    1 AVVELTDENFEEEVLESDKPVLVDFWAPWCGPCKMLAPVLEE--LAAEYGGKVKFVKVDVDENPELAAQFGVRSIPTLLL 78

                 ....
gi 163776139 222 FPKG 225
Cdd:COG3118   79 FKDG 82

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 163776139  25 VIDLTPDTFD-DIINGDRPALVEFFAPWCGHCKSLAPTWEELGTAYAsqKDVIIAKVDASEHRDLGSRFGVTGFPTLKFF 103
Cdd:COG3118    2 VVELTDENFEeEVLESDKPVLVDFWAPWCGPCKMLAPVLEELAAEYG--GKVKFVKVDVDENPELAAQFGVRSIPTLLLF 79

                 ...
gi 163776139 104 PKG 106
Cdd:COG3118   80 KDG 82

thioredoxin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 163776139 151 FDAIaLDTDKDVLVEFYAPWCGHCKSVAPIYEKAGLAFAneeNVVVAKVDADKHSELASKFGVSGFPTFKFFPKGSTEAE 230
Cdd:PTZ00051  11 FEST-LSQNELVIVDFYAEWCGPCKRIAPFYEECSKEYT---KMVFVKVDVDELSEVAEKENITSMPTFKVFKNGSVVDT 86

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 163776139  24 DVIDLTPDTFDDIINGDR-PALVEFFAPWCGHCKSLAPTWEELGTAYASQKDVIIAKVDASE-HRDLGSRFGVTGFPTLK 101
Cdd:cd02998    1 NVVELTDSNFDKVVGDDKkDVLVEFYAPWCGHCKNLAPEYEKLAAVFANEDDVVIAKVDADEaNKDLAKKYGVSGFPTLK 80

                         90       100
                 ....*....|....*....|....
gi 163776139 102 FFPKGSTEPEDYKGGRALNDLADF 125
Cdd:cd02998   81 FFPKGSTEPVKYEGGRDLEDLVKF 104

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 163776139  26 IDLTPDTFDDIINGDRPALVEFFAPWCGHCKSLAPTWEELGTAYASQKDVIIAKVDASEHRDLGSRFGVTGFPTLKFFPK 105
Cdd:cd02961    1 VELTDDNFDELVKDSKDVLVEFYAPWCGHCKALAPEYEKLAKELKGDGKVVVAKVDCTANNDLCSEYGVRGYPTIKLFPN 80

                         90       100
                 ....*....|....*....|.
gi 163776139 106 GSTEPEDYKGGRALNDLADFM 126
Cdd:cd02961   81 GSKEPVKYEGPRTLESLVEFI 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 163776139 144 KVLDPTNFDAIALDtDKDVLVEFYAPWCGHCKSVAPIYEKAGLAFANEENVVVAKVDADKHSELASKFGVSGFPTFKFFP 223
Cdd:cd02961    1 VELTDDNFDELVKD-SKDVLVEFYAPWCGHCKALAPEYEKLAKELKGDGKVVVAKVDCTANNDLCSEYGVRGYPTIKLFP 79

                         90       100
                 ....*....|....*....|..
gi 163776139 224 KGSTEAEDYSSGRELQSFLTFL 245
Cdd:cd02961   80 NGSKEPVKYEGPRTLESLVEFI 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 163776139 143 VKVLDPTNFDAIALDTDKDVLVEFYAPWCGHCKSVAPIYEKAGLAFANEENVVVAKVDADKhSELASKFGVSGFPTFKFF 222
Cdd:cd02995    2 VKVVVGKNFDEVVLDSDKDVLVEFYAPWCGHCKALAPIYEELAEKLKGDDNVVIAKMDATA-NDVPSEFVVDGFPTILFF 80

                         90       100
                 ....*....|....*....|....
gi 163776139 223 PKGS-TEAEDYSSGRELQSFLTFL 245
Cdd:cd02995   81 PAGDkSNPIKYEGDRTLEDLIKFI 104

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 163776139   23 SDVIDLTPDTFDDIINGDRPALVEFFAPWCGHCKSLAPTWEELGTAYASQ-KDVIIAKVDASEHRDLGSRFGVTGFPTLK 101
Cdd:TIGR01130   1 EDVLVLTKDNFDDFIKSHEFVLVEFYAPWCGHCKSLAPEYEKAADELKKKgPPIKLAKVDATEEKDLAQKYGVSGYPTLK 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 163776139  102 FFPKGSTEPEDYKGGRALNDLADFMLQKTGyrariqQDVSHVKVLDptnfDAIALDTDKDVLVEFY 167
Cdd:TIGR01130  81 IFRNGEDSVSDYNGPRDADGIVKYMKKQSG------PAVKEIETVA----DLEAFLADDDVVVIGF 136

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 163776139  31 DTFDDII-NGDRPALVEFFAPWCGHCKSLAPTWEELGTAYASQKDVIIAKVDASEHrDLGSRFGVTGFPTLKFFPKGS-T 108
Cdd:cd02995    8 KNFDEVVlDSDKDVLVEFYAPWCGHCKALAPIYEELAEKLKGDDNVVIAKMDATAN-DVPSEFVVDGFPTILFFPAGDkS 86

                         90
                 ....*....|....*...
gi 163776139 109 EPEDYKGGRALNDLADFM 126
Cdd:cd02995   87 NPIKYEGDRTLEDLIKFI 104

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 163776139   25 VIDLTPDTFDDII-NGDRPALVEFFAPWCGHCKSLAPTWEELGTAYAsqKDVIIAKVDASEHRDLGSRFGVTGFPTLKFF 103
Cdd:pfam00085   2 VVVLTDANFDEVVqKSSKPVLVDFYAPWCGPCKMLAPEYEELAQEYK--GNVVFAKVDVDENPDLASKYGVRGYPTLIFF 79

                          90       100
                  ....*....|....*....|...
gi 163776139  104 PKGStEPEDYKGGRALNDLADFM 126
Cdd:pfam00085  80 KNGQ-PVDDYVGARPKDALAAFL 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 163776139   31 DTFDDIING-DRPALVEFFAPWCGHCKSLAPTWEELGTAYAS-QKDVIIAKVDASEHrDLGSrFGVTGFPTLKFFPKGS- 107
Cdd:TIGR01130 354 KNFDEIVLDeTKDVLVEFYAPWCGHCKNLAPIYEELAEKYKDaESDVVIAKMDATAN-DVPP-FEVEGFPTIKFVPAGKk 431

                          90
                  ....*....|....*....
gi 163776139  108 TEPEDYKGGRALNDLADFM 126
Cdd:TIGR01130 432 SEPVPYDGDRTLEDFSKFI 450

Endoplasmic reticulum protein ERp29, C-terminal domain; ERp29 is a ubiquitously expressed endoplasmic reticulum protein found in mammals. ERp29 is comprised of two domains. This domain, the C-terminal domain, has an all helical fold. ERp29 is thought to form part of the thyroglobulin folding complex.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 163776139  264 GRHERLDALAQNFVSG---DRDTLLAEAQKIANELGDI---FAKYYVKVMEKIKSDGDGYAAKELERLQRILDGGNVKTD 337
Cdd:pfam07749   1 GRIEELDALAAEFVAAakdERKELLEEAKKAAEKLKEAekkYAKYYVKVMEKILEKGEEYVEKELARLEKLLAKGKLSPE 80

                          90
                  ....*....|....*
gi 163776139  338 RKDNFFIRRNILKQF 352
Cdd:pfam07749  81 KKDELQIRLNILRSF 95

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 163776139  25 VIDLTPDTFDDII-NGDRPALVEFFAPWCGHCKSLAPTWEELGTAYASQKDVIIAKVDASEHRDLGSRFGVTGFPTLKFF 103
Cdd:cd03002    2 VYELTPKNFDKVVhNTNYTTLVEFYAPWCGHCKNLKPEYAKAAKELDGLVQVAAVDCDEDKNKPLCGKYGVQGFPTLKVF 81

                         90       100
                 ....*....|....*....|....*...
gi 163776139 104 PKGSTE----PEDYKGGRALNDLADFML 127
Cdd:cd03002   82 RPPKKAskhaVEDYNGERSAKAIVDFVL 109

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 163776139 142 HVKVLDPTNFD-AIAldtDKDVLVEFYAPWCGHCKSVAPIYEKAGLAFANE-ENVVVAKVDADKHSELASKFGVSGFPTF 219
Cdd:cd03005    1 GVLELTEDNFDhHIA---EGNHFVKFFAPWCGHCKRLAPTWEQLAKKFNNEnPSVKIAKVDCTQHRELCSEFQVRGYPTL 77

                         90       100
                 ....*....|....*....|....*.
gi 163776139 220 KFFpKGSTEAEDYSSGRELQSFLTFL 245
Cdd:cd03005   78 LLF-KDGEKVDKYKGTRDLDSLKEFV 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 163776139 142 HVKVLDPTNFDAIALDTDKDVLVEFYAPWCGHCKSVAPIYEKAGLAFANEENVVVAKVDADKHSELASKFGVSGFPTFKF 221
Cdd:cd03002    1 PVYELTPKNFDKVVHNTNYTTLVEFYAPWCGHCKNLKPEYAKAAKELDGLVQVAAVDCDEDKNKPLCGKYGVQGFPTLKV 80

                         90       100
                 ....*....|....*....|....*..
gi 163776139 222 FPKGSTE----AEDYSSGRELQSFLTF 244
Cdd:cd03002   81 FRPPKKAskhaVEDYNGERSAKAIVDF 107

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 163776139  24 DVIDLTPDTFDDIINGDRPALVEFFAPWCGHCKSLAPTWEELGTAYASQKDVIIAKVDA--SEHRDLGSRFGVTGFPTLK 101
Cdd:cd02997    1 DVVHLTDEDFRKFLKKEKHVLVMFYAPWCGHCKKMKPEFTKAATELKEDGKGVLAAVDCtkPEHDALKEEYNVKGFPTFK 80

                         90       100
                 ....*....|....*....|....*
gi 163776139 102 FFPKGSTEpEDYKGGRALNDLADFM 126
Cdd:cd02997   81 YFENGKFV-EKYEGERTAEDIIEFM 104

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 163776139 150 NFDAIaLDTDKDVLVEFYAPWCGHCKSVAPIYEKaglaFANEE-NVVVAKVDADKHSELASKFGVSGFPTFKFF 222
Cdd:cd02947    2 EFEEL-IKSAKPVVVDFWAPWCGPCKAIAPVLEE----LAEEYpKVKFVKVDVDENPELAEEYGVRSIPTFLFF 70

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 163776139   28 LTPDTFDDII-NGDRPALVEFFAPWCGHCKSLAPTWEELGTAYASqkDVIIAKVDASEHRDLGSRFGVTGFPTLKFFPKG 106
Cdd:TIGR01068   1 LTDANFDETIaSSDKPVLVDFWAPWCGPCKMIAPILEELAKEYEG--KVKFVKLNVDENPDIAAKYGIRSIPTLLLFKNG 78

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 163776139  23 SDVIDLTPDTFDD-IINGDRPALVEFFAPWCGHCKSLAPTWEELGTAYASQkdVIIAKVDASEHRDLGSRFGVTGFPTLK 101
Cdd:cd03004    1 PSVITLTPEDFPElVLNRKEPWLVDFYAPWCGPCQALLPELRKAARALKGK--VKVGSVDCQKYESLCQQANIRAYPTIR 78

                         90
                 ....*....|....
gi 163776139 102 FFPKGSTEPEDYKG 115
Cdd:cd03004   79 LYPGNASKYHSYNG 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 163776139 163 LVEFYAPWCGHCKSVAPIYEKAGLAFANE-ENVVVAKVDADKHSELASKFGVSGFPTFKFFpKGSTeAEDYSSGRELQSF 241
Cdd:cd03000   19 LVDFYAPWCGHCKKLEPVWNEVGAELKSSgSPVRVGKLDATAYSSIASEFGVRGYPTIKLL-KGDL-AYNYRGPRTKDDI 96

                 ....*...
gi 163776139 242 LTFLNEKA 249
Cdd:cd03000   97 VEFANRVA 104

ERp29 and ERp38, C-terminal domain; composed of the protein disulfide isomerase (PDI)-like proteins ERp29 and ERp38. ERp29 (also called ERp28) is a ubiquitous endoplasmic reticulum (ER)-resident protein expressed in high levels in secretory cells. It contains a redox inactive TRX-like domain at the N-terminus. The expression profile of ERp29 suggests a role in secretory protein production, distinct from that of PDI. It has also been identified as a member of the thyroglobulin folding complex and is essential in regulating the secretion of thyroglobulin. The Drosophila homolog, Wind, is the product of windbeutel, an essential gene in the development of dorsal-ventral patterning. Wind is required for correct targeting of Pipe, a Golgi-resident type II transmembrane protein with homology to 2-O-sulfotransferase. ERp38 is a P5-like protein, first isolated from alfalfa (the cDNA clone was named G1), which contains two redox active TRX domains at the N-terminus, like human P5. However, unlike human P5, ERp38 also contains a C-terminal domain with homology to the C-terminal domain of ERp29. It may be a glucose-regulated protein. The function of the all-helical C-terminal domain of ERp29 and ERp38 remains unclear. The C-terminal domain of Wind is thought to provide a distinct site required for interaction with its substrate, Pipe.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 163776139 267 ERLDALAQNFVSGDRDT---LLAEAQKIANELG---DIFAKYYVKVMEKIKSDGDGYAAKELERLQRILDGGNVKTDRKD 340
Cdd:cd00238    2 EELDELAKEFVDASDEErkeLLEKVKEAVEKLKeaeAKYAKYYVKVMEKILEKGEDYVEKELARLERLLEKKGLAPEKAD 81

                         90
                 ....*....|..
gi 163776139 341 NFFIRRNILKQF 352
Cdd:cd00238   82 ELTRRLNILRSF 93

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 163776139  23 SDVIDLTPDTFDDIINGDrpALVEFFAPWCGHCKSLAPTWEELGTaYASQKDVIIAKVDASEHRDLGSRFGVTGFPTlkF 102
Cdd:cd02994    1 SNVVELTDSNWTLVLEGE--WMIEFYAPWCPACQQLQPEWEEFAD-WSDDLGINVAKVDVTQEPGLSGRFFVTALPT--I 75

                         90       100
                 ....*....|....*....|....*.
gi 163776139 103 FPKGSTEPEDYKGGRALNDLADFMLQ 128
Cdd:cd02994   76 YHAKDGVFRRYQGPRDKEDLISFIEE 101

Thioredoxin domain-containing protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 163776139   6 SMLAAGVLALVMAAATASDVIDLTPDTFDDIINGDR-----PALVEFFAPWCGHCKSLAPTWEELGTAYASQkdVIIAKV 80
Cdd:PTZ00443  13 GLIADEATNVKLDAEDANALVLLNDKNFEKLTQASTgattgPWFVKFYAPWCSHCRKMAPAWERLAKALKGQ--VNVADL 90

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 163776139  81 DASEHRDLGSRFGVTGFPTLKFFPKGSTepEDYKGG-RALNDLADFML 127
Cdd:PTZ00443  91 DATRALNLAKRFAIKGYPTLLLFDKGKM--YQYEGGdRSTEKLAAFAL 136