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 20070125    24 DHVLVLRKSNFAEALAAHKYLLVEFYAPWCGHCKALAPEYAKAAGKLKAEGSEIRLAKVDATEESDLAQQYGVRGYPTIK 103
Cdd:TIGR01130   1 EDVLVLTKDNFDDFIKSHEFVLVEFYAPWCGHCKSLAPEYEKAADELKKKGPPIKLAKVDATEEKDLAQKYGVSGYPTLK 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20070125   104 FFRNGDTaSPKEYTAGREADDIVNWLKKRTGPAATTLPDGAAAESLVESSEVAVIGFFKDVESDSAKQFLQAAEAIDDIP 183
Cdd:TIGR01130  81 IFRNGED-SVSDYNGPRDADGIVKYMKKQSGPAVKEIETVADLEAFLADDDVVVIGFFKDLDSELNDTFLSVAEKLRDVY 159

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20070125   184 FGITSNSDV--FSKYQLDKDGVVLFKKFDEGRN----NFEGEVTKENLLDFIKHNQLPLVIEFTEQTAPKIFGGEIKTHI 257
Cdd:TIGR01130 160 FFFAHSSDVaaFAKLGAFPDSVVLFKPKDEDEKfskvDGEMDTDVSDLEKFIRAESLPLVGEFTQETAAKYFESGPLVVL 239

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20070125   258 LLFLPKSVSDYDGKLSNFKTAAESFKGK-ILFIFIDSDhtDNQRILEFFGLKKEECPAVRLITLeEEMTKYKPESEELTA 336
Cdd:TIGR01130 240 YYNVDESLDPFEELRNRFLEAAKKFRGKfVNFAVADEE--DFGRELEYFGLKAEKFPAVAIQDL-EGNKKYPMDQEEFSS 316

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20070125   337 ERITEFCHRFLEGKIKPHLMSQELPEDwDKQPVKVLVGKNFEDVAFDEKKNVFVEFYAPWCGHCKQLAPIWDKLGETYKD 416
Cdd:TIGR01130 317 ENLEAFVKDFLDGKLKPYLKSEPIPED-DEGPVKVLVGKNFDEIVLDETKDVLVEFYAPWCGHCKNLAPIYEELAEKYKD 395

                         410       420       430       440       450
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 20070125   417 HE-NIVIAKMDSTANEVEAVKVHSFPTLKFFPASADRTVIDYNGERTLDGFKKFLESGG 474
Cdd:TIGR01130 396 AEsDVVIAKMDATANDVPPFEVEGFPTIKFVPAGKKSEPVPYDGDRTLEDFSKFIAKHA 454

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 20070125    24 DHVLVLRKSNFAEALAAHKYLLVEFYAPWCGHCKALAPEYAKAAGKLKAEGSEIRLAKVDATEESDLAQQYGVRGYPTIK 103
Cdd:TIGR01130   1 EDVLVLTKDNFDDFIKSHEFVLVEFYAPWCGHCKSLAPEYEKAADELKKKGPPIKLAKVDATEEKDLAQKYGVSGYPTLK 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20070125   104 FFRNGDTaSPKEYTAGREADDIVNWLKKRTGPAATTLPDGAAAESLVESSEVAVIGFFKDVESDSAKQFLQAAEAIDDIP 183
Cdd:TIGR01130  81 IFRNGED-SVSDYNGPRDADGIVKYMKKQSGPAVKEIETVADLEAFLADDDVVVIGFFKDLDSELNDTFLSVAEKLRDVY 159

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20070125   184 FGITSNSDV--FSKYQLDKDGVVLFKKFDEGRN----NFEGEVTKENLLDFIKHNQLPLVIEFTEQTAPKIFGGEIKTHI 257
Cdd:TIGR01130 160 FFFAHSSDVaaFAKLGAFPDSVVLFKPKDEDEKfskvDGEMDTDVSDLEKFIRAESLPLVGEFTQETAAKYFESGPLVVL 239

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20070125   258 LLFLPKSVSDYDGKLSNFKTAAESFKGK-ILFIFIDSDhtDNQRILEFFGLKKEECPAVRLITLeEEMTKYKPESEELTA 336
Cdd:TIGR01130 240 YYNVDESLDPFEELRNRFLEAAKKFRGKfVNFAVADEE--DFGRELEYFGLKAEKFPAVAIQDL-EGNKKYPMDQEEFSS 316

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20070125   337 ERITEFCHRFLEGKIKPHLMSQELPEDwDKQPVKVLVGKNFEDVAFDEKKNVFVEFYAPWCGHCKQLAPIWDKLGETYKD 416
Cdd:TIGR01130 317 ENLEAFVKDFLDGKLKPYLKSEPIPED-DEGPVKVLVGKNFDEIVLDETKDVLVEFYAPWCGHCKNLAPIYEELAEKYKD 395

                         410       420       430       440       450
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 20070125   417 HE-NIVIAKMDSTANEVEAVKVHSFPTLKFFPASADRTVIDYNGERTLDGFKKFLESGG 474
Cdd:TIGR01130 396 AEsDVVIAKMDATANDVPPFEVEGFPTIKFVPAGKKSEPVPYDGDRTLEDFSKFIAKHA 454

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 20070125 368 PVKVLVGKNFEDVAFDEKKNVFVEFYAPWCGHCKQLAPIWDKLGETYKDHENIVIAKMDSTANEVEAVK-VHSFPTLKFF 446
Cdd:cd02995   1 PVKVVVGKNFDEVVLDSDKDVLVEFYAPWCGHCKALAPIYEELAEKLKGDDNVVIAKMDATANDVPSEFvVDGFPTILFF 80

                        90       100
                ....*....|....*....|....
gi 20070125 447 PASADRTVIDYNGERTLDGFKKFL 470
Cdd:cd02995  81 PAGDKSNPIKYEGDRTLEDLIKFI 104

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 20070125  25 HVLVLRKSNF-AEALAAHKYLLVEFYAPWCGHCKALAPEYAKAAGKLkaeGSEIRLAKVDATEESDLAQQYGVRGYPTIK 103
Cdd:COG3118   1 AVVELTDENFeEEVLESDKPVLVDFWAPWCGPCKMLAPVLEELAAEY---GGKVKFVKVDVDENPELAAQFGVRSIPTLL 77

                        90       100
                ....*....|....*....|....*....
gi 20070125 104 FFRNGDtasPKEYTAG-READDIVNWLKK 131
Cdd:COG3118  78 LFKDGQ---PVDRFVGaLPKEQLREFLDK 103

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 20070125    24 DHVLVLRKSNFAEALAAHKYLLVEFYAPWCGHCKALAPEYAKAAGKLKAEGSEIRLAKVDATEESDLAQQYGVRGYPTIK 103
Cdd:TIGR01130   1 EDVLVLTKDNFDDFIKSHEFVLVEFYAPWCGHCKSLAPEYEKAADELKKKGPPIKLAKVDATEEKDLAQKYGVSGYPTLK 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20070125   104 FFRNGDTaSPKEYTAGREADDIVNWLKKRTGPAATTLPDGAAAESLVESSEVAVIGFFKDVESDSAKQFLQAAEAIDDIP 183
Cdd:TIGR01130  81 IFRNGED-SVSDYNGPRDADGIVKYMKKQSGPAVKEIETVADLEAFLADDDVVVIGFFKDLDSELNDTFLSVAEKLRDVY 159

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20070125   184 FGITSNSDV--FSKYQLDKDGVVLFKKFDEGRN----NFEGEVTKENLLDFIKHNQLPLVIEFTEQTAPKIFGGEIKTHI 257
Cdd:TIGR01130 160 FFFAHSSDVaaFAKLGAFPDSVVLFKPKDEDEKfskvDGEMDTDVSDLEKFIRAESLPLVGEFTQETAAKYFESGPLVVL 239

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20070125   258 LLFLPKSVSDYDGKLSNFKTAAESFKGK-ILFIFIDSDhtDNQRILEFFGLKKEECPAVRLITLeEEMTKYKPESEELTA 336
Cdd:TIGR01130 240 YYNVDESLDPFEELRNRFLEAAKKFRGKfVNFAVADEE--DFGRELEYFGLKAEKFPAVAIQDL-EGNKKYPMDQEEFSS 316

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20070125   337 ERITEFCHRFLEGKIKPHLMSQELPEDwDKQPVKVLVGKNFEDVAFDEKKNVFVEFYAPWCGHCKQLAPIWDKLGETYKD 416
Cdd:TIGR01130 317 ENLEAFVKDFLDGKLKPYLKSEPIPED-DEGPVKVLVGKNFDEIVLDETKDVLVEFYAPWCGHCKNLAPIYEELAEKYKD 395

                         410       420       430       440       450
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 20070125   417 HE-NIVIAKMDSTANEVEAVKVHSFPTLKFFPASADRTVIDYNGERTLDGFKKFLESGG 474
Cdd:TIGR01130 396 AEsDVVIAKMDATANDVPPFEVEGFPTIKFVPAGKKSEPVPYDGDRTLEDFSKFIAKHA 454

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 20070125 368 PVKVLVGKNFEDVAFDEKKNVFVEFYAPWCGHCKQLAPIWDKLGETYKDHENIVIAKMDSTANEVEAVK-VHSFPTLKFF 446
Cdd:cd02995   1 PVKVVVGKNFDEVVLDSDKDVLVEFYAPWCGHCKALAPIYEELAEKLKGDDNVVIAKMDATANDVPSEFvVDGFPTILFF 80

                        90       100
                ....*....|....*....|....
gi 20070125 447 PASADRTVIDYNGERTLDGFKKFL 470
Cdd:cd02995  81 PAGDKSNPIKYEGDRTLEDLIKFI 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 20070125  27 LVLRKSNFAEALAAHKYLLVEFYAPWCGHCKALAPEYAKAAGKLKAEGSeIRLAKVDATEESDLAQQYGVRGYPTIKFFR 106
Cdd:cd02961   1 VELTDDNFDELVKDSKDVLVEFYAPWCGHCKALAPEYEKLAKELKGDGK-VVVAKVDCTANNDLCSEYGVRGYPTIKLFP 79

                        90       100
                ....*....|....*....|...
gi 20070125 107 NGDTaSPKEYTAGREADDIVNWL 129
Cdd:cd02961  80 NGSK-EPVKYEGPRTLESLVEFI 101

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 20070125 369 VKVLVGKNFEDVAFDEKKNVFVEFYAPWCGHCKQLAPIWDKLGETYKDHENIVIAKMDSTANEVEAVK---VHSFPTLKF 445
Cdd:cd02998   2 VVELTDSNFDKVVGDDKKDVLVEFYAPWCGHCKNLAPEYEKLAAVFANEDDVVIAKVDADEANKDLAKkygVSGFPTLKF 81

                        90       100
                ....*....|....*....|....*
gi 20070125 446 FPASADRTViDYNGERTLDGFKKFL 470
Cdd:cd02998  82 FPKGSTEPV-KYEGGRDLEDLVKFV 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 20070125  26 VLVLRKSNFAEALAAHKYL-LVEFYAPWCGHCKALAPEYAKAAGKLKAegsEIRLAKVDATEESDLAQQYGVRGYPTIKF 104
Cdd:cd03001   2 VVELTDSNFDKKVLNSDDVwLVEFYAPWCGHCKNLAPEWKKAAKALKG---IVKVGAVDADVHQSLAQQYGVRGFPTIKV 78

                        90       100
                ....*....|....*....|....
gi 20070125 105 FRNGdTASPKEYTAGREADDIVNW 128
Cdd:cd03001  79 FGAG-KNSPQDYQGGRTAKAIVSA 101

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 20070125    26 VLVLRKSNFAEALA-AHKYLLVEFYAPWCGHCKALAPEYAKAAGKLKAegsEIRLAKVDATEESDLAQQYGVRGYPTIKF 104
Cdd:pfam00085   2 VVVLTDANFDEVVQkSSKPVLVDFYAPWCGPCKMLAPEYEELAQEYKG---NVVFAKVDVDENPDLASKYGVRGYPTLIF 78

                          90       100
                  ....*....|....*....|....*..
gi 20070125   105 FRNGDTasPKEYTAGREADDIVNWLKK 131
Cdd:pfam00085  79 FKNGQP--VDDYVGARPKDALAAFLKA 103

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 20070125  26 VLVLRKSNFAEALAAHKYLLVEFYAPWCGHCKALAPEYAKAAGKLKAEGSeIRLAKVDAT--EESDLAQQYGVRGYPTIK 103
Cdd:cd02997   2 VVHLTDEDFRKFLKKEKHVLVMFYAPWCGHCKKMKPEFTKAATELKEDGK-GVLAAVDCTkpEHDALKEEYNVKGFPTFK 80

                        90       100
                ....*....|....*....|....*.
gi 20070125 104 FFRNGDTAspKEYTAGREADDIVNWL 129
Cdd:cd02997  81 YFENGKFV--EKYEGERTAEDIIEFM 104

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 20070125  25 HVLVLRKSNFAEALAAhKYLLVEFYAPWCGHCKALAPEYAKAAGKLKAEGSEIRLAKVDATEESDLAQQYGVRGYPTIKF 104
Cdd:cd03005   1 GVLELTEDNFDHHIAE-GNHFVKFFAPWCGHCKRLAPTWEQLAKKFNNENPSVKIAKVDCTQHRELCSEFQVRGYPTLLL 79

                        90       100
                ....*....|....*....|....*
gi 20070125 105 FRNGDTASpkEYTAGREADDIVNWL 129
Cdd:cd03005  80 FKDGEKVD--KYKGTRDLDSLKEFV 102

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 20070125  45 LVEFYAPWCGHCKALAPEYAKAAGKLKAeGSEIRLAKVDATeESDLAQQYGVRGYPTIKFFRNGDTASPKEYTAGREADD 124
Cdd:cd02995  22 LVEFYAPWCGHCKALAPIYEELAEKLKG-DDNVVIAKMDAT-ANDVPSEFVVDGFPTILFFPAGDKSNPIKYEGDRTLED 99

                ....*
gi 20070125 125 IVNWL 129
Cdd:cd02995 100 LIKFI 104

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 20070125  25 HVLVLRKSNF-AEALAAHKYLLVEFYAPWCGHCKALAPEYAKAAGKLkaeGSEIRLAKVDATEESDLAQQYGVRGYPTIK 103
Cdd:COG3118   1 AVVELTDENFeEEVLESDKPVLVDFWAPWCGPCKMLAPVLEELAAEY---GGKVKFVKVDVDENPELAAQFGVRSIPTLL 77

                        90       100
                ....*....|....*....|....*....
gi 20070125 104 FFRNGDtasPKEYTAG-READDIVNWLKK 131
Cdd:COG3118  78 LFKDGQ---PVDRFVGaLPKEQLREFLDK 103

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 20070125  25 HVLVLRKSNFAE-ALAAHKYLLVEFYAPWCGHCKALAPEYAKAAGKLKAegsEIRLAKVDATEESDLAQQYGVRGYPTIK 103
Cdd:cd03004   2 SVITLTPEDFPElVLNRKEPWLVDFYAPWCGPCQALLPELRKAARALKG---KVKVGSVDCQKYESLCQQANIRAYPTIR 78

                        90       100
                ....*....|....*....|....*..
gi 20070125 104 FFrNGDTASPKEYTA-GREADDIVNWL 129
Cdd:cd03004  79 LY-PGNASKYHSYNGwHRDADSILEFI 104

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 20070125 369 VKVLVGKNFED-VAfdeKKNVFVEFYAPWCGHCKQLAPIWDKLG-ETYKDHENIVIAKMDSTANE--VEAVKVHSFPTLK 444
Cdd:cd03005   2 VLELTEDNFDHhIA---EGNHFVKFFAPWCGHCKRLAPTWEQLAkKFNNENPSVKIAKVDCTQHRelCSEFQVRGYPTLL 78

                        90       100
                ....*....|....*....|....*.
gi 20070125 445 FFpaSADRTVIDYNGERTLDGFKKFL 470
Cdd:cd03005  79 LF--KDGEKVDKYKGTRDLDSLKEFV 102

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 20070125  32 SNFAEALAAHKYLLVEFYAPWCGHCKALAPEYAKAAgklkAEGSEIRLAKVDATEESDLAQQYGVRGYPTIKFFRNG 108
Cdd:cd02947   1 EEFEELIKSAKPVVVDFWAPWCGPCKAIAPVLEELA----EEYPKVKFVKVDVDENPELAEEYGVRSIPTFLFFKNG 73

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 20070125 372 LVGKNFEDvAFDEKKNVFVEFYAPWCGHCKQLAPIWDKLGETYKDHENIVIAKMDSTANEVEAVK----VHSFPTLKFFp 447
Cdd:cd02997   5 LTDEDFRK-FLKKEKHVLVMFYAPWCGHCKKMKPEFTKAATELKEDGKGVLAAVDCTKPEHDALKeeynVKGFPTFKYF- 82

                        90       100
                ....*....|....*....|...
gi 20070125 448 aSADRTVIDYNGERTLDGFKKFL 470
Cdd:cd02997  83 -ENGKFVEKYEGERTAEDIIEFM 104

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 20070125  24 DHVLVLRKSNFAEALA-AHKYLLVEFYAPWCGHCKALAPEYAKAAGKLKAEGSEIRLAKVDATEES--DLAQQYGVRGYP 100
Cdd:cd02992   1 DPVIVLDAASFNSALLgSPSAWLVEFYASWCGHCRAFAPTWKKLARDLRKWRPVVRVAAVDCADEEnvALCRDFGVTGYP 80

                ....*.
gi 20070125 101 TIKFFR 106
Cdd:cd02992  81 TLRYFP 86

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 20070125 368 PVKVLVGKNFEDVAFDEKKNVFVEFYAPWCGHCKQLAPIWDKLGETYKDHENIV-IAKMDSTANEVEAV----KVHSFPT 442
Cdd:cd02992   2 PVIVLDAASFNSALLGSPSAWLVEFYASWCGHCRAFAPTWKKLARDLRKWRPVVrVAAVDCADEENVALcrdfGVTGYPT 81

                ....*..
gi 20070125 443 LKFFPAS 449
Cdd:cd02992  82 LRYFPPF 88

PDIa family, endoplasmic reticulum protein 44 (ERp44) subfamily; ERp44 is an ER-resident protein, induced during stress, involved in thiol-mediated ER retention. It contains an N-terminal TRX domain, similar to that of PDIa, with a CXFS motif followed by two redox inactive TRX-like domains, homologous to the b and b' domains of PDI. The CXFS motif in the N-terminal domain allows ERp44 to form stable reversible mixed disulfides with its substrates. Through this activity, ERp44 mediates the ER localization of Ero1alpha, a protein that oxidizes protein disulfide isomerases into their active form. ERp44 also prevents the secretion of unassembled cargo protein with unpaired cysteines. It also modulates the activity of inositol 1,4,5-triphosphate type I receptor (IP3R1), an intracellular channel protein that mediates calcium release from the ER to the cytosol.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20070125  33 NFAEALAAHKYLLVEFYAPWCGHCKALAPEYAKAAGKLKAEGSE---IRLAKVDATEESDLAQQYGVRGYPTIKFFRNGD 109
Cdd:cd02996  10 NIDDILQSAELVLVNFYADWCRFSQMLHPIFEEAAAKIKEEFPDagkVVWGKVDCDKESDIADRYRINKYPTLKLFRNGM 89

                        90       100
                ....*....|....*....|
gi 20070125 110 tASPKEYTAGREADDIVNWL 129
Cdd:cd02996  90 -MMKREYRGQRSVEALAEFV 108

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 20070125 369 VKVLVGKNFEDVAFDEKKNVFVEFYAPWCGHCKQLAPIWDKLGETYKdhENIVIAKMDSTANE--VEAVKVHSFPTLKFF 446
Cdd:cd03004   3 VITLTPEDFPELVLNRKEPWLVDFYAPWCGPCQALLPELRKAARALK--GKVKVGSVDCQKYEslCQQANIRAYPTIRLY 80

                        90
                ....*....|....
gi 20070125 447 PASADrTVIDYNGE 460
Cdd:cd03004  81 PGNAS-KYHSYNGW 93

thioredoxin 2; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 20070125   32 SNFAEALAAHKYLLVEFYAPWCGHCKALAPEYAKAAgklKAEGSEIRLAKVDATEESDLAQQYGVRGYPTIKFFRNG 108
Cdd:PRK10996  43 ETLDKLLQDDLPVVIDFWAPWCGPCRNFAPIFEDVA---AERSGKVRFVKVNTEAERELSARFRIRSIPTIMIFKNG 116