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 224493972  82 GLYELSASNFELHVAQGDHFIKFFAPWCGHCKALAPTWEQLALGLEH-SETVKIGKVDCTQHYELCSGNQVRGYPTLLWF 160
Cdd:cd03005    1 GVLELTEDNFDHHIAEGNHFVKFFAPWCGHCKRLAPTWEQLAKKFNNeNPSVKIAKVDCTQHRELCSEFQVRGYPTLLLF 80

                         90       100
                 ....*....|....*....|..
gi 224493972 161 RDGKKVDQYKGKRDLESLREYV 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 224493972   2 EDAKVYVAKVDCTAHSDVCSAQGVRGYPTLKLFKPGQEAVKYQGPRDFQTLENWM 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 224493972  82 GLYELSASNFELHVAQGDHFIKFFAPWCGHCKALAPTWEQLALGLEH-SETVKIGKVDCTQHYELCSGNQVRGYPTLLWF 160
Cdd:cd03005    1 GVLELTEDNFDHHIAEGNHFVKFFAPWCGHCKRLAPTWEQLAKKFNNeNPSVKIAKVDCTQHRELCSEFQVRGYPTLLLF 80

                         90       100
                 ....*....|....*....|..
gi 224493972 161 RDGKKVDQYKGKRDLESLREYV 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 224493972  219 LTENNFDDTIAEG-ITFIKFYAPWCGHCKTLAPTWEELSkKEFPGLAGVKIAEVDCTAERNICSKYSVRGYPTLLLFRGG 297
Cdd:TIGR01126   1 LTASNFDEIVLSNkDVLVEFYAPWCGHCKNLAPEYEKLA-KELKKDPKIVLAKVDATAEKDLASRFGVSGFPTIKFFPKG 79

                          90       100
                  ....*....|....*....|...
gi 224493972  298 KKVSEHSGGRDLDSLHRFVLSQA 320
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 224493972  216 VLALTENNFDDTIA--EGITFIKFYAPWCGHCKTLAPTWEELSKkEFPGlaGVKIAEVDCTAERNICSKYSVRGYPTLLL 293
Cdd:pfam00085   2 VVVLTDANFDEVVQksSKPVLVDFYAPWCGPCKMLAPEYEELAQ-EYKG--NVVFAKVDVDENPDLASKYGVRGYPTLIF 78

                          90       100
                  ....*....|....*....|...
gi 224493972  294 FRGGKKVSEHSGGRDLDSLHRFV 316
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 224493972   2 EDAKVYVAKVDCTAHSDVCSAQGVRGYPTLKLFKPGQEAVKYQGPRDFQTLENWM 56
Cdd:cd03005   48 ENPSVKIAKVDCTQHRELCSEFQVRGYPTLLLFKDGEKVDKYKGTRDLDSLKEFV 102

disulphide isomerase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 224493972 216 VLALTENNFDDTIAEG-ITFIKFYAPWCGHCKTLAPTWEELSKKEFPGLAGVKIAEVDCTAERNICSKYSVRGYPTLLLF 294
Cdd:PTZ00102  34 VTVLTDSTFDKFITENeIVLVKFYAPWCGHCKRLAPEYKKAAKMLKEKKSEIVLASVDATEEMELAQEFGVRGYPTIKFF 113

                         90       100
                 ....*....|....*....|..
gi 224493972 295 RGGKKVsEHSGGRDLDSLHRFV 316
Cdd:PTZ00102 114 NKGNPV-NYSGGRTADGIVSWI 134

disulphide isomerase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 224493972  75 SAPELKQGLYELSASNFELHVAQGDH-FIKFFAPWCGHCKALAPTWEQLALGL-EHSETVKIGKVDCTQHYELCSGNQVR 152
Cdd:PTZ00102  26 EEHFISEHVTVLTDSTFDKFITENEIvLVKFYAPWCGHCKRLAPEYKKAAKMLkEKKSEIVLASVDATEEMELAQEFGVR 105

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 224493972 153 GYPTLLWFRDGKKVDqYKGKRDLESLREYVEsqlQRTETGATETVTPSEAPVLAAE 208
Cdd:PTZ00102 106 GYPTIKFFNKGNPVN-YSGGRTADGIVSWIK---KLTGPAVTEVESASEIKLIAKK 157

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

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 224493972   5 KVYVAKVDCTAHSDVCSAQGVRGYPTLKLFKPGQEAVKYQGPRDFQTLENWM 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 224493972  82 GLYELSASNFELHVAQGDHFIKFFAPWCGHCKALAPTWEQLALGLEH-SETVKIGKVDCTQHYELCSGNQVRGYPTLLWF 160
Cdd:cd03005    1 GVLELTEDNFDHHIAEGNHFVKFFAPWCGHCKRLAPTWEQLAKKFNNeNPSVKIAKVDCTQHRELCSEFQVRGYPTLLLF 80

                         90       100
                 ....*....|....*....|..
gi 224493972 161 RDGKKVDQYKGKRDLESLREYV 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 224493972  85 ELSASNFELHVAQG-DHFIKFFAPWCGHCKALAPTWEQLALGLEHSETVKIGKVDCTQHYELCSGNQVRGYPTLLWFRDG 163
Cdd:cd02961    2 ELTDDNFDELVKDSkDVLVEFYAPWCGHCKALAPEYEKLAKELKGDGKVVVAKVDCTANNDLCSEYGVRGYPTIKLFPNG 81

                         90       100
                 ....*....|....*....|
gi 224493972 164 -KKVDQYKGKRDLESLREYV 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 224493972 219 LTENNFDDTIAEG-ITFIKFYAPWCGHCKTLAPTWEELSKKeFPGLAGVKIAEVDCTAERNICSKYSVRGYPTLLLFRGG 297
Cdd:cd02961    3 LTDDNFDELVKDSkDVLVEFYAPWCGHCKALAPEYEKLAKE-LKGDGKVVVAKVDCTANNDLCSEYGVRGYPTIKLFPNG 81

                         90       100
                 ....*....|....*....|
gi 224493972 298 -KKVSEHSGGRDLDSLHRFV 316
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 224493972  216 VLALTENNFDDTIAEG-ITFIKFYAPWCGHCKTLAPTWE----ELSKKEFPglagVKIAEVDCTAERNICSKYSVRGYPT 290
Cdd:TIGR01130   3 VLVLTKDNFDDFIKSHeFVLVEFYAPWCGHCKSLAPEYEkaadELKKKGPP----IKLAKVDATEEKDLAQKYGVSGYPT 78

                          90       100       110
                  ....*....|....*....|....*....|.
gi 224493972  291 LLLFRGGKK-VSEHSGGRDLDSLHRFVLSQA 320
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 224493972 216 VLALTENNFDDTIAEGI--TFIKFYAPWCGHCKTLAPTWEELSkKEFPGLAGVKIAEVDCTAE-RNICSKYSVRGYPTLL 292
Cdd:cd02998    2 VVELTDSNFDKVVGDDKkdVLVEFYAPWCGHCKNLAPEYEKLA-AVFANEDDVVIAKVDADEAnKDLAKKYGVSGFPTLK 80

                         90       100
                 ....*....|....*....|....*
gi 224493972 293 LF-RGGKKVSEHSGGRDLDSLHRFV 316
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 224493972  85 ELSASNFELHVAQG--DHFIKFFAPWCGHCKALAPTWEQLALGLEHSETVKIGKVDCTQ-HYELCSGNQVRGYPTLLWF- 160
Cdd:cd02998    4 ELTDSNFDKVVGDDkkDVLVEFYAPWCGHCKNLAPEYEKLAAVFANEDDVVIAKVDADEaNKDLAKKYGVSGFPTLKFFp 83

                         90       100
                 ....*....|....*....|..
gi 224493972 161 RDGKKVDQYKGKRDLESLREYV 182
Cdd:cd02998   84 KGSTEPVKYEGGRDLEDLVKFV 105

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 224493972   85 ELSASNFELHVAQ--GDHFIKFFAPWCGHCKALAPTWEQLALglEHSETVKIGKVDCTQHYELCSGNQVRGYPTLLWFRD 162
Cdd:pfam00085   4 VLTDANFDEVVQKssKPVLVDFYAPWCGPCKMLAPEYEELAQ--EYKGNVVFAKVDVDENPDLASKYGVRGYPTLIFFKN 81

                          90       100
                  ....*....|....*....|..
gi 224493972  163 GKKVDQYKGKRDLESLREYVES 184
Cdd:pfam00085  82 GQPVDDYVGARPKDALAAFLKA 103

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 224493972 219 LTENNFDDTIAEGI--TFIKFYAPWCGHCKTLAPTWEELSKKeFPGLAGVKIAEVDCTAerN-ICSKYSVRGYPTLLLFR 295
Cdd:cd02995    5 VVGKNFDEVVLDSDkdVLVEFYAPWCGHCKALAPIYEELAEK-LKGDDNVVIAKMDATA--NdVPSEFVVDGFPTILFFP 81

                         90       100
                 ....*....|....*....|...
gi 224493972 296 GGKK--VSEHSGGRDLDSLHRFV 316
Cdd:cd02995   82 AGDKsnPIKYEGDRTLEDLIKFI 104

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 224493972 216 VLALTENNFDDTIA--EGITFIKFYAPWCGHCKTLAPTWEELSkKEFPGLagVKIAEVDCTAERN--ICSKYSVRGYPTL 291
Cdd:cd03002    2 VYELTPKNFDKVVHntNYTTLVEFYAPWCGHCKNLKPEYAKAA-KELDGL--VQVAAVDCDEDKNkpLCGKYGVQGFPTL 78

                         90       100       110
                 ....*....|....*....|....*....|.
gi 224493972 292 LLFRGGKKVSEHS-----GGRDLDSLHRFVL 317
Cdd:cd03002   79 KVFRPPKKASKHAvedynGERSAKAIVDFVL 109

disulphide isomerase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 224493972 216 VLALTENNFDDTIAEG-ITFIKFYAPWCGHCKTLAPTWEELSKKEFPGLAGVKIAEVDCTAERNICSKYSVRGYPTLLLF 294
Cdd:PTZ00102  34 VTVLTDSTFDKFITENeIVLVKFYAPWCGHCKRLAPEYKKAAKMLKEKKSEIVLASVDATEEMELAQEFGVRGYPTIKFF 113

                         90       100
                 ....*....|....*....|..
gi 224493972 295 RGGKKVsEHSGGRDLDSLHRFV 316
Cdd:PTZ00102 114 NKGNPV-NYSGGRTADGIVSWI 134

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 224493972  85 ELSASNFELHVAQGDH--FIKFFAPWCGHCKALAPTWEQLALglEHSETVKIGKVDCTQHYELCSGNQVRGYPTLLWFRD 162
Cdd:COG3118    4 ELTDENFEEEVLESDKpvLVDFWAPWCGPCKMLAPVLEELAA--EYGGKVKFVKVDVDENPELAAQFGVRSIPTLLLFKD 81

                         90       100
                 ....*....|....*....|....
gi 224493972 163 GKKVDQYKGKRDLESLREYVESQL 186
Cdd:COG3118   82 GQPVDRFVGALPKEQLREFLDKVL 105

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 224493972  85 ELSASNFELHVAQGDH--FIKFFAPWCGHCKALAPTWEQLALGLEhsETVKIGKVDCTQHYELCSGNQVRGYPTLLWFRD 162
Cdd:cd03001    4 ELTDSNFDKKVLNSDDvwLVEFYAPWCGHCKNLAPEWKKAAKALK--GIVKVGAVDADVHQSLAQQYGVRGFPTIKVFGA 81

                         90
                 ....*....|....*..
gi 224493972 163 GKKVDQ-YKGKRDLESL 178
Cdd:cd03001   82 GKNSPQdYQGGRTAKAI 98

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 224493972 223 NFDDTIAE-GITFIKFYAPWCGHCKTLAPTWEELSKKEfpglAGVKIAEVDCTAERNICSKYSVRGYPTLLLFRGGKKVS 301
Cdd:cd02947    2 EFEELIKSaKPVVVDFWAPWCGPCKAIAPVLEELAEEY----PKVKFVKVDVDENPELAEEYGVRSIPTFLFFKNGKEVD 77

                         90
                 ....*....|....*
gi 224493972 302 EHSGGRDLDSLHRFV 316
Cdd:cd02947   78 RVVGADPKEELEEFL 92

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 224493972  84 YELSASNFELHVAQGDH--FIKFFAPWCGHCKALAPTWEQLALGLehSETVKIGKVDCTQ--HYELCSGNQVRGYPTLLW 159
Cdd:cd03002    3 YELTPKNFDKVVHNTNYttLVEFYAPWCGHCKNLKPEYAKAAKEL--DGLVQVAAVDCDEdkNKPLCGKYGVQGFPTLKV 80

                         90       100
                 ....*....|....*....|....*...
gi 224493972 160 FRDGKKVDQ-----YKGKRDLESLREYV 182
Cdd:cd03002   81 FRPPKKASKhavedYNGERSAKAIVDFV 108

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 224493972  219 LTENNFDDTIAEG--ITFIKFYAPWCGHCKTLAPTWEELSKKEFPglaGVKIAEVDCTAERNICSKYSVRGYPTLLLFRG 296
Cdd:TIGR01068   1 LTDANFDETIASSdkPVLVDFWAPWCGPCKMIAPILEELAKEYEG---KVKFVKLNVDENPDIAAKYGIRSIPTLLLFKN 77

                  ....
gi 224493972  297 GKKV 300
Cdd:TIGR01068  78 GKEV 81

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 224493972 216 VLALTENNFDDTIAEGITF--IKFYAPWCGHCKTLAPTWEELSK--KEFPGLagVKIAEVDCTAERN--ICSKYSVRGYP 289
Cdd:cd02992    3 VIVLDAASFNSALLGSPSAwlVEFYASWCGHCRAFAPTWKKLARdlRKWRPV--VRVAAVDCADEENvaLCRDFGVTGYP 80

                         90
                 ....*....|
gi 224493972 290 TLLLFRGGKK 299
Cdd:cd02992   81 TLRYFPPFSK 90

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 224493972 101 FIKFFAPWCGHCKALAPTWEQLALGLEHSET-VKIGKVDCTQHYELCSGNQVRGYPTLLWFRDGKKVDqYKGKRDLESLR 179
Cdd:cd03000   19 LVDFYAPWCGHCKKLEPVWNEVGAELKSSGSpVRVGKLDATAYSSIASEFGVRGYPTIKLLKGDLAYN-YRGPRTKDDIV 97

                 ..
gi 224493972 180 EY 181
Cdd:cd03000   98 EF 99

Thioredoxin domain-containing protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 224493972  78 ELKQGLYELSASNFE------LHVAQGDHFIKFFAPWCGHCKALAPTWEQLALGLEHseTVKIGKVDCTQHYELCSGNQV 151
Cdd:PTZ00443  27 EDANALVLLNDKNFEkltqasTGATTGPWFVKFYAPWCSHCRKMAPAWERLAKALKG--QVNVADLDATRALNLAKRFAI 104

                         90       100       110
                 ....*....|....*....|....*....|.
gi 224493972 152 RGYPTLLWFRDGkKVDQYK-GKRDLESLREY 181
Cdd:PTZ00443 105 KGYPTLLLFDKG-KMYQYEgGDRSTEKLAAF 134

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 224493972  86 LSASNFELHVAQGD-HFIKFFAPWCGHCKALAPTWEQLALGLEHseTVKIGKVDCTQHYELCSGNQVRGYPTLLWFRDGK 164
Cdd:cd03003    6 LDRGDFDAAVNSGEiWFVNFYSPRCSHCHDLAPTWREFAKEMDG--VIRIGAVNCGDDRMLCRSQGVNSYPSLYVFPSGM 83

                         90
                 ....*....|....*..
gi 224493972 165 KVDQYKGKRDLESLREY 181
Cdd:cd03003   84 NPEKYYGDRSKESLVKF 100

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 224493972  85 ELSASNFE--LHVAQGDHFIKFFAPWCGHCKALAPTWEQLA-LGLEHSETVKIGKVDCTQ--HYELCSGNQVRGYPTLLW 159
Cdd:cd02992    5 VLDAASFNsaLLGSPSAWLVEFYASWCGHCRAFAPTWKKLArDLRKWRPVVRVAAVDCADeeNVALCRDFGVTGYPTLRY 84

                         90       100
                 ....*....|....*....|....*..
gi 224493972 160 F----RDGKKVDQYKG-KRDLESLREY 181
Cdd:cd02992   85 FppfsKEATDGLKQEGpERDVNELREA 111

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 224493972  85 ELSASNFELhVAQGDHFIKFFAPWCGHCKALAPTWEQLAlglEHSET--VKIGKVDCTQHYELCSGNQVRGYPTLLWFRD 162
Cdd:cd02994    5 ELTDSNWTL-VLEGEWMIEFYAPWCPACQQLQPEWEEFA---DWSDDlgINVAKVDVTQEPGLSGRFFVTALPTIYHAKD 80