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 1958665846  56 DVVHIDSEkDFRRLLKKEeKPLLMMFYAPWCSMCKRIMPHFQKAATQVR--GHTVLAGMNVYPPEFENIKEEYNVRGYPT 133
Cdd:cd02997     1 DVVHLTDE-DFRKFLKKE-KHVLVMFYAPWCGHCKKMKPEFTKAATELKedGKGVLAAVDCTKPEHDALKEEYNVKGFPT 78

                          90       100
                  ....*....|....*....|....*..
gi 1958665846 134 ICYFEKGRFLFQYENYGsTAEDIVEWL 160
Cdd:cd02997    79 FKYFENGKFVEKYEGER-TAEDIIEFM 104

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
                  ....*....|....*....|....*....|....*....|...
gi 1958665846   1 MKVDLSPKDKKIELFHYQDGAFHMQYDRAVTLKSIVAFLKDPK 43
Cdd:cd03067    70 LKVDPSSKPKPVELKHYKDGDFHTEYNRQLTFKSMVAFLRDPE 112

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 1958665846  56 DVVHIDSEkDFRRLLKKEeKPLLMMFYAPWCSMCKRIMPHFQKAATQVR--GHTVLAGMNVYPPEFENIKEEYNVRGYPT 133
Cdd:cd02997     1 DVVHLTDE-DFRKFLKKE-KHVLVMFYAPWCGHCKKMKPEFTKAATELKedGKGVLAAVDCTKPEHDALKEEYNVKGFPT 78

                          90       100
                  ....*....|....*....|....*..
gi 1958665846 134 ICYFEKGRFLFQYENYGsTAEDIVEWL 160
Cdd:cd02997    79 FKYFENGKFVEKYEGER-TAEDIIEFM 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 1958665846 185 LTDEDFDQFVKEHSSVLVMFHAPWCGHCKKMKPEFESAAEVLHGDAeSSGVLAAVDATINEALAERFHISAFPTLKYFKN 264
Cdd:TIGR01130   6 LTKDNFDDFIKSHEFVLVEFYAPWCGHCKSLAPEYEKAADELKKKG-PPIKLAKVDATEEKDLAQKYGVSGYPTLKIFRN 84

                          90       100
                  ....*....|....*....|.
gi 1958665846 265 GEQQAVP--ALRTKKKFIEWM 283
Cdd:TIGR01130  85 GEDSVSDynGPRDADGIVKYM 105

disulphide isomerase; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958665846  72 KEEKPLLMMFYAPWCSMCKRIMPHFQKAATQVR---GHTVLAGMNVypPEFENIKEEYNVRGYPTICYFEKGrflfQYEN 148
Cdd:PTZ00102   47 TENEIVLVKFYAPWCGHCKRLAPEYKKAAKMLKekkSEIVLASVDA--TEEMELAQEFGVRGYPTIKFFNKG----NPVN 120

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958665846 149 Y--GSTAEDIVEWLKNPQPPQPQVPETPWADE-------GGSVYHLTDEDFDQFVK---------EHSSVLVMFHAP--- 207
Cdd:PTZ00102  121 YsgGRTADGIVSWIKKLTGPAVTEVESASEIKliakkifVAFYGEYTSKDSELYKKfeevadkhrEHAKFFVKKHEGknk 200

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958665846 208 -----------------------------------------------------W-CGHCK---KMKPEFESAAEVLHgdA 230
Cdd:PTZ00102  201 iyvlhkdeegvelfmgktkeeleefvstesfplfaeinaenyrryissgkdlvWfCGTTEdydKYKSVVRKVARKLR--E 278

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958665846 231 ESSGVLAAVDATINEAlAERFHISAFPTLKYFKNGE----QQAVPALRTKKKFIEWMQNPEAPPPPEPTW-----EEQQT 301
Cdd:PTZ00102  279 KYAFVWLDTEQFGSHA-KEHLLIEEFPGLAYQSPAGryllPPAKESFDSVEALIEFFKDVEAGKVEKSIKsepipEEQDG 357

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958665846 302 SVLHLVGDNFRE-TLKKKKHTLVMFYAPWCPHCKKVIPHFTATADAFKDDRKIACAAVDcvKDKNQDLCQQESVKAYPTF 380
Cdd:PTZ00102  358 PVKVVVGNTFEEiVFKSDKDVLLEIYAPWCGHCKNLEPVYNELGEKYKDNDSIIVAKMN--GTANETPLEEFSWSAFPTI 435

                         410       420
                  ....*....|....*....|....*.
gi 1958665846 381 HYYHYG-KLVEKYESDRTELGFTSFI 405
Cdd:PTZ00102  436 LFVKAGeRTPIPYEGERTVEGFKEFV 461

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 1958665846 181 SVYHLTDEDFDQFV-KEHSSVLVMFHAPWCGHCKKMKPEFESAAEVLHGDAessgVLAAVDATINEALAERFHISAFPTL 259
Cdd:COG3118     1 AVVELTDENFEEEVlESDKPVLVDFWAPWCGPCKMLAPVLEELAAEYGGKV----KFVKVDVDENPELAAQFGVRSIPTL 76

                          90       100
                  ....*....|....*....|....*..
gi 1958665846 260 KYFKNGEQQA-VPALRTKKKFIEWMQN 285
Cdd:COG3118    77 LLFKDGQPVDrFVGALPKEQLREFLDK 103

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 1958665846 181 SVYHLTDEDFDQFV-KEHSSVLVMFHAPWCGHCKKMKPEFESAAEVLHGDAessgVLAAVDATINEALAERFHISAFPTL 259
Cdd:pfam00085   1 VVVVLTDANFDEVVqKSSKPVLVDFYAPWCGPCKMLAPEYEELAQEYKGNV----VFAKVDVDENPDLASKYGVRGYPTL 76

                  ....*..
gi 1958665846 260 KYFKNGE 266
Cdd:pfam00085  77 IFFKNGQ 83

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 1958665846  57 VVHIDSEKDFRRLLKKEEKPLLMMFYAPWCSMCKRIMPHFQKAATQVRGHTVLAGMNVypPEFENIKEEYNVRGYPTICY 136
Cdd:pfam00085   1 VVVVLTDANFDEVVQKSSKPVLVDFYAPWCGPCKMLAPEYEELAQEYKGNVVFAKVDV--DENPDLASKYGVRGYPTLIF 78

                          90       100
                  ....*....|....*....|....*
gi 1958665846 137 FEKGRFLFQYENyGSTAEDIVEWLK 161
Cdd:pfam00085  79 FKNGQPVDDYVG-ARPKDALAAFLK 102

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 1958665846 302 SVLHLVGDNFRE-TLKKKKHTLVMFYAPWCPHCKKVIPHFTATADAFKDdrKIACAAVDCvkDKNQDLCQQESVKAYPTF 380
Cdd:COG3118     1 AVVELTDENFEEeVLESDKPVLVDFWAPWCGPCKMLAPVLEELAAEYGG--KVKFVKVDV--DENPELAAQFGVRSIPTL 76

                          90       100
                  ....*....|....*....|....*.
gi 1958665846 381 HYYHYGKLVEKYESDRTELGFTSFIR 406
Cdd:COG3118    77 LLFKDGQPVDRFVGALPKEQLREFLD 102

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1958665846  62 SEKDFRRLLKKEEKPLLMMFYAPWCSMCKRIMPHFQKAATQVRGHTVLAGMNVypPEFENIKEEYNVRGYPTICYFEKG 140
Cdd:TIGR01068   2 TDANFDETIASSDKPVLVDFWAPWCGPCKMIAPILEELAKEYEGKVKFVKLNV--DENPDIAAKYGIRSIPTLLLFKNG 78

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 1958665846  56 DVVHIDSEkDFRRLLKKEeKPLLMMFYAPWCSMCKRIMPHFQKAATQVR--GHTVLAGMNVYPPEFENIKEEYNVRGYPT 133
Cdd:cd02997     1 DVVHLTDE-DFRKFLKKE-KHVLVMFYAPWCGHCKKMKPEFTKAATELKedGKGVLAAVDCTKPEHDALKEEYNVKGFPT 78

                          90       100
                  ....*....|....*....|....*..
gi 1958665846 134 ICYFEKGRFLFQYENYGsTAEDIVEWL 160
Cdd:cd02997    79 FKYFENGKFVEKYEGER-TAEDIIEFM 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 1958665846 304 LHLVGDNFRETLKKKKHTLVMFYAPWCPHCKKVIPHFTATADAFKDDRKIACAAVDCvkDKNQDLCQQESVKAYPTFHYY 383
Cdd:cd02961     1 VELTDDNFDELVKDSKDVLVEFYAPWCGHCKALAPEYEKLAKELKGDGKVVVAKVDC--TANNDLCSEYGVRGYPTIKLF 78

                          90       100
                  ....*....|....*....|...
gi 1958665846 384 HYG-KLVEKYESDRTELGFTSFI 405
Cdd:cd02961    79 PNGsKEPVKYEGPRTLESLVEFI 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 1958665846 185 LTDEDFDQFVKEHSSVLVMFHAPWCGHCKKMKPEFESAAEVLHGDAeSSGVLAAVDATINEALAERFHISAFPTLKYFKN 264
Cdd:TIGR01130   6 LTKDNFDDFIKSHEFVLVEFYAPWCGHCKSLAPEYEKAADELKKKG-PPIKLAKVDATEEKDLAQKYGVSGYPTLKIFRN 84

                          90       100
                  ....*....|....*....|.
gi 1958665846 265 GEQQAVP--ALRTKKKFIEWM 283
Cdd:TIGR01130  85 GEDSVSDynGPRDADGIVKYM 105

disulphide isomerase; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958665846 185 LTDEDFDQFVKEHSSVLVMFHAPWCGHCKKMKPEFESAAEVLhGDAESSGVLAAVDATINEALAERFHISAFPTLKYFKN 264
Cdd:PTZ00102   37 LTDSTFDKFITENEIVLVKFYAPWCGHCKRLAPEYKKAAKML-KEKKSEIVLASVDATEEMELAQEFGVRGYPTIKFFNK 115

                          90       100
                  ....*....|....*....|
gi 1958665846 265 GEQQAVPALRTKKKFIEWMQ 284
Cdd:PTZ00102  116 GNPVNYSGGRTADGIVSWIK 135

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 1958665846 182 VYHLTDEDFDQFVKEHSS-VLVMFHAPWCGHCKKMKPEFESAAEVLHGDAEssgvLAAVDATINEALAERFHISAFPTLK 260
Cdd:cd03001     2 VVELTDSNFDKKVLNSDDvWLVEFYAPWCGHCKNLAPEWKKAAKALKGIVK----VGAVDADVHQSLAQQYGVRGFPTIK 77

                          90       100
                  ....*....|....*....|....*
gi 1958665846 261 YFKNGEQQAVP--ALRTKKKFIEWM 283
Cdd:cd03001    78 VFGAGKNSPQDyqGGRTAKAIVSAA 102

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 1958665846 302 SVLHLVGDNFRETLKK-KKHTLVMFYAPWCPHCKKVIPHFTATADAFKDDRKIACAAVDCvKDKNQDLCQQESVKAYPTF 380
Cdd:cd02998     1 NVVELTDSNFDKVVGDdKKDVLVEFYAPWCGHCKNLAPEYEKLAAVFANEDDVVIAKVDA-DEANKDLAKKYGVSGFPTL 79

                          90       100
                  ....*....|....*....|....*.
gi 1958665846 381 HYYHYGKLV-EKYESDRTELGFTSFI 405
Cdd:cd02998    80 KFFPKGSTEpVKYEGGRDLEDLVKFV 105

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 1958665846 181 SVYHLTDEDFDQFV-KEHSSVLVMFHAPWCGHCKKMKPEFESAAEVLHGDAessgVLAAVDATINEALAERFHISAFPTL 259
Cdd:COG3118     1 AVVELTDENFEEEVlESDKPVLVDFWAPWCGPCKMLAPVLEELAAEYGGKV----KFVKVDVDENPELAAQFGVRSIPTL 76

                          90       100
                  ....*....|....*....|....*..
gi 1958665846 260 KYFKNGEQQA-VPALRTKKKFIEWMQN 285
Cdd:COG3118    77 LLFKDGQPVDrFVGALPKEQLREFLDK 103

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 1958665846 181 SVYHLTDEDFDQFV-KEHSSVLVMFHAPWCGHCKKMKPEFESAAEVLHGDAessgVLAAVDATINEALAERFHISAFPTL 259
Cdd:pfam00085   1 VVVVLTDANFDEVVqKSSKPVLVDFYAPWCGPCKMLAPEYEELAQEYKGNV----VFAKVDVDENPDLASKYGVRGYPTL 76

                  ....*..
gi 1958665846 260 KYFKNGE 266
Cdd:pfam00085  77 IFFKNGQ 83

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 1958665846 182 VYHLTDEDFDQFVK-EHSSVLVMFHAPWCGHCKKMKPEFESAAEVLHGDAEssgvLAAV--DATINEALAERFHISAFPT 258
Cdd:cd03002     2 VYELTPKNFDKVVHnTNYTTLVEFYAPWCGHCKNLKPEYAKAAKELDGLVQ----VAAVdcDEDKNKPLCGKYGVQGFPT 77

                  ....*
gi 1958665846 259 LKYFK 263
Cdd:cd03002    78 LKVFR 82

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 1958665846 181 SVYHLTDEDFDQFVKEHS-SVLVMFHAPWCGHCKKMKPEFESAAEVLHGDaeSSGVLAAVDATINEALAERFhISAFPTL 259
Cdd:cd02995     1 PVKVVVGKNFDEVVLDSDkDVLVEFYAPWCGHCKALAPIYEELAEKLKGD--DNVVIAKMDATANDVPSEFV-VDGFPTI 77

                          90       100
                  ....*....|....*....|....*..
gi 1958665846 260 KYFKNGEQQAV---PALRTKKKFIEWM 283
Cdd:cd02995    78 LFFPAGDKSNPikyEGDRTLEDLIKFI 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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958665846 188 EDFDQFVKEHSSVLVMFHAPWCGHCKKMKPEFESAAEvLHGDAessgVLAAVDATINEALAERFHISAFPTLKYFKNGEQ 267
Cdd:cd02947     1 EEFEELIKSAKPVVVDFWAPWCGPCKAIAPVLEELAE-EYPKV----KFVKVDVDENPELAEEYGVRSIPTFLFFKNGKE 75

                          90
                  ....*....|....*...
gi 1958665846 268 QA-VPALRTKKKFIEWMQ 284
Cdd:cd02947    76 VDrVVGADPKEELEEFLE 93

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 1958665846  11 KIELFHYQDGAFHMQYDRAVTLKSIVAFLKDPKGPPlweedpgakdVVHIDSEKDFRRLlkkEEKPLLMMFY--APWCSM 88
Cdd:TIGR01130 183 LFKPKDEDEKFSKVDGEMDTDVSDLEKFIRAESLPL----------VGEFTQETAAKYF---ESGPLVVLYYnvDESLDP 249

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958665846  89 CKRIMPHFQKAATQVRGHTVL---AGMNVYPPEFENIkeEYNVRGYPTI-CYFEKGRFLFQYENYGSTAEDIVEW----L 160
Cdd:TIGR01130 250 FEELRNRFLEAAKKFRGKFVNfavADEEDFGRELEYF--GLKAEKFPAVaIQDLEGNKKYPMDQEEFSSENLEAFvkdfL 327

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958665846 161 KNPQPPQPQVPETPWADEGgSVYHLTDEDFDQFV-KEHSSVLVMFHAPWCGHCKKMKPEFESAAEVLHgDAESSGVLAAV 239
Cdd:TIGR01130 328 DGKLKPYLKSEPIPEDDEG-PVKVLVGKNFDEIVlDETKDVLVEFYAPWCGHCKNLAPIYEELAEKYK-DAESDVVIAKM 405

                         250       260
                  ....*....|....*....|....*..
gi 1958665846 240 DATINEalAERFHISAFPTLKYFKNGE 266
Cdd:TIGR01130 406 DATAND--VPPFEVEGFPTIKFVPAGK 430

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 1958665846 302 SVLHLVGDNFRETLKKKKHT-LVMFYAPWCPHCKKVIPHFTATADAFKDDRK-IACAAVDCVKDKNQDLCQQESVKAYPT 379
Cdd:cd02992     2 PVIVLDAASFNSALLGSPSAwLVEFYASWCGHCRAFAPTWKKLARDLRKWRPvVRVAAVDCADEENVALCRDFGVTGYPT 81

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1958665846 380 FHYYHY----GKLVEKYEsdrtelGFTSFIRTLRE 410
Cdd:cd02992    82 LRYFPPfskeATDGLKQE------GPERDVNELRE 110

disulphide isomerase; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958665846 303 VLHLVGDNFRETLKKKKHTLVMFYAPWCPHCKKVIPHFTATADAFKDDR-KIACAAVDCvkDKNQDLCQQESVKAYPTFH 381
Cdd:PTZ00102   34 VTVLTDSTFDKFITENEIVLVKFYAPWCGHCKRLAPEYKKAAKMLKEKKsEIVLASVDA--TEEMELAQEFGVRGYPTIK 111

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 1958665846 382 YYHYGKLVEkYESDRTELGFTSFIRTLREGDLKRLEKRRED 422
Cdd:PTZ00102  112 FFNKGNPVN-YSGGRTADGIVSWIKKLTGPAVTEVESASEI 151

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 1958665846 309 DNFRETLKKKKHTLVMFYAPWCPHCKKVIPHFTATADAFKddrKIACAAVDCvkDKNQDLCQQESVKAYPTFHYYHYGKL 388
Cdd:cd02947     1 EEFEELIKSAKPVVVDFWAPWCGPCKAIAPVLEELAEEYP---KVKFVKVDV--DENPELAEEYGVRSIPTFLFFKNGKE 75

                          90
                  ....*....|....*..
gi 1958665846 389 VEKYESDRTELGFTSFI 405
Cdd:cd02947    76 VDRVVGADPKEELEEFL 92

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 1958665846  57 VVHIDSEKDFRRLLKKEEKPLLMMFYAPWCSMCKRIMPHFQKAATQVRGHTVLAGMNVypPEFENIKEEYNVRGYPTICY 136
Cdd:pfam00085   1 VVVVLTDANFDEVVQKSSKPVLVDFYAPWCGPCKMLAPEYEELAQEYKGNVVFAKVDV--DENPDLASKYGVRGYPTLIF 78