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 34784103  83 GLYELTATNFKSHIAKGSHFVKFFAPWCGHCKAMAPTWEQLASSFEHSDS-IKISKVDCTQHYEVCSDNQVRGYPTLLFF 161
Cdd:cd03005   1 GVLELTEDNFDHHIAEGNHFVKFFAPWCGHCKRLAPTWEQLAKKFNNENPsVKIAKVDCTQHRELCSEFQVRGYPTLLLF 80

                        90       100
                ....*....|....*....|..
gi 34784103 162 TDGEKIDQYRGKRDLDSFKEFV 183
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 34784103   2 EAPPAYVVKVDCTKDTKFCSsEHGIRGYPTLKLFKPEQEAVKYQGPRDLQALENWM 57
Cdd:cd03005  48 ENPSVKIAKVDCTQHRELCS-EFQVRGYPTLLLFKDGEKVDKYKGTRDLDSLKEFV 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 34784103  83 GLYELTATNFKSHIAKGSHFVKFFAPWCGHCKAMAPTWEQLASSFEHSDS-IKISKVDCTQHYEVCSDNQVRGYPTLLFF 161
Cdd:cd03005   1 GVLELTEDNFDHHIAEGNHFVKFFAPWCGHCKRLAPTWEQLAKKFNNENPsVKIAKVDCTQHRELCSEFQVRGYPTLLLF 80

                        90       100
                ....*....|....*....|..
gi 34784103 162 TDGEKIDQYRGKRDLDSFKEFV 183
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 34784103   222 LTESNFDETVAKG-LSFIKFYAPWCGHCKNLAPTWDDLSqKEFPGLTDVKIAKVDCTVERTLCNRFSVRGYPTLLMFRAG 300
Cdd:TIGR01126   1 LTASNFDEIVLSNkDVLVEFYAPWCGHCKNLAPEYEKLA-KELKKDPKIVLAKVDATAEKDLASRFGVSGFPTIKFFPKG 79

                          90       100
                  ....*....|....*....|...
gi 34784103   301 QQGEEHNGGRDLESLHSFIMKQA 323
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 34784103    86 ELTATNFKSHIAKGS--HFVKFFAPWCGHCKAMAPTWEQLASsfEHSDSIKISKVDCTQHYEVCSDNQVRGYPTLLFFTD 163
Cdd:pfam00085   4 VLTDANFDEVVQKSSkpVLVDFYAPWCGPCKMLAPEYEELAQ--EYKGNVVFAKVDVDENPDLASKYGVRGYPTLIFFKN 81

                          90       100
                  ....*....|....*....|.
gi 34784103   164 GEKIDQYRGKRDLDSFKEFVD 184
Cdd:pfam00085  82 GQPVDDYVGARPKDALAAFLK 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 34784103  86 ELTATNFKSHIAKGSH--FVKFFAPWCGHCKAMAPTWEQLASsfEHSDSIKISKVDCTQHYEVCSDNQVRGYPTLLFFTD 163
Cdd:COG3118   4 ELTDENFEEEVLESDKpvLVDFWAPWCGPCKMLAPVLEELAA--EYGGKVKFVKVDVDENPELAAQFGVRSIPTLLLFKD 81

                        90       100
                ....*....|....*....|....
gi 34784103 164 GEKIDQYRGKRDLDSFKEFVDNHV 187
Cdd:COG3118  82 GQPVDRFVGALPKEQLREFLDKVL 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 34784103 218 NVLVLTESNFDETV--AKGLSFIKFYAPWCGHCKNLAPTWDDLSqKEFPGltDVKIAKVDCTVERTLCNRFSVRGYPTLL 295
Cdd:COG3118   1 AVVELTDENFEEEVleSDKPVLVDFWAPWCGPCKMLAPVLEELA-AEYGG--KVKFVKVDVDENPELAAQFGVRSIPTLL 77

                        90       100
                ....*....|....*....|....
gi 34784103 296 MFRAGQQGEEHNGGRDLESLHSFI 319
Cdd:COG3118  78 LFKDGQPVDRFVGALPKEQLREFL 101

Thioredoxin domain-containing protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 34784103   84 LYELTATNFK------SHIAKGSHFVKFFAPWCGHCKAMAPTWEQLASSFEhsDSIKISKVDCTQHYEVCSDNQVRGYPT 157
Cdd:PTZ00443  32 LVLLNDKNFEkltqasTGATTGPWFVKFYAPWCSHCRKMAPAWERLAKALK--GQVNVADLDATRALNLAKRFAIKGYPT 109

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 34784103  158 LLFFTDGeKIDQYR-GKRDLDSFKEFVDNHVKAAESKDEPE 197
Cdd:PTZ00443 110 LLLFDKG-KMYQYEgGDRSTEKLAAFALGDFKKALGAPVPA 149

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

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 34784103   8 VVKVDCTKDTKFcSSEHGIRGYPTLKLFKPEQEAVKYQGPRDLQALENWM 57
Cdd:COG3118  53 FVKVDVDENPEL-AAQFGVRSIPTLLLFKDGQPVDRFVGALPKEQLREFL 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 34784103  83 GLYELTATNFKSHIAKGSHFVKFFAPWCGHCKAMAPTWEQLASSFEHSDS-IKISKVDCTQHYEVCSDNQVRGYPTLLFF 161
Cdd:cd03005   1 GVLELTEDNFDHHIAEGNHFVKFFAPWCGHCKRLAPTWEQLAKKFNNENPsVKIAKVDCTQHRELCSEFQVRGYPTLLLF 80

                        90       100
                ....*....|....*....|..
gi 34784103 162 TDGEKIDQYRGKRDLDSFKEFV 183
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 34784103   222 LTESNFDETVAKG-LSFIKFYAPWCGHCKNLAPTWDDLSqKEFPGLTDVKIAKVDCTVERTLCNRFSVRGYPTLLMFRAG 300
Cdd:TIGR01126   1 LTASNFDEIVLSNkDVLVEFYAPWCGHCKNLAPEYEKLA-KELKKDPKIVLAKVDATAEKDLASRFGVSGFPTIKFFPKG 79

                          90       100
                  ....*....|....*....|...
gi 34784103   301 QQGEEHNGGRDLESLHSFIMKQA 323
Cdd:TIGR01126  80 SKPVDYEGGRDLEAIVEFVNEKS 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 34784103 220 LVLTESNFDETVAKG-LSFIKFYAPWCGHCKNLAPTWDDLSqKEFPGLTDVKIAKVDCTVERTLCNRFSVRGYPTLLMFR 298
Cdd:cd02961   1 VELTDDNFDELVKDSkDVLVEFYAPWCGHCKALAPEYEKLA-KELKGDGKVVVAKVDCTANNDLCSEYGVRGYPTIKLFP 79

                        90       100
                ....*....|....*....|..
gi 34784103 299 AG-QQGEEHNGGRDLESLHSFI 319
Cdd:cd02961  80 NGsKEPVKYEGPRTLESLVEFI 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 34784103    86 ELTATNFKSHIAKGSH-FVKFFAPWCGHCKAMAPTWEQLASSF-EHSDSIKISKVDCTQHYEVCSDNQVRGYPTLLFFTD 163
Cdd:TIGR01130   5 VLTKDNFDDFIKSHEFvLVEFYAPWCGHCKSLAPEYEKAADELkKKGPPIKLAKVDATEEKDLAQKYGVSGYPTLKIFRN 84

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 34784103   164 GEKIDQ-YRGKRDLDSF----------------------------------------KEFVDNHVKAAESKDE------- 195
Cdd:TIGR01130  85 GEDSVSdYNGPRDADGIvkymkkqsgpavkeietvadleafladddvvvigffkdldSELNDTFLSVAEKLRDvyfffah 164

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 34784103   196 ---------------------PEKEEE--------------------HTHEIPPSAE----------------------- 211
Cdd:TIGR01130 165 ssdvaafaklgafpdsvvlfkPKDEDEkfskvdgemdtdvsdlekfiRAESLPLVGEftqetaakyfesgplvvlyynvd 244

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 34784103       --------------------------------------------------------------------------------
Cdd:TIGR01130 245 esldpfeelrnrfleaakkfrgkfvnfavadeedfgreleyfglkaekfpavaiqdlegnkkypmdqeefssenleafvk 324

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 34784103   212 ----------------PEKQESNVLVLTESNFDETV--AKGLSFIKFYAPWCGHCKNLAPTWDDLSQKEFPGLTDVKIAK 273
Cdd:TIGR01130 325 dfldgklkpylksepiPEDDEGPVKVLVGKNFDEIVldETKDVLVEFYAPWCGHCKNLAPIYEELAEKYKDAESDVVIAK 404

                         410       420       430       440       450
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 34784103   274 VDCTVertlcN---RFSVRGYPTLLMFRAGQQGE--EHNGGRDLESLHSFIMKQARDEL 327
Cdd:TIGR01130 405 MDATA-----NdvpPFEVEGFPTIKFVPAGKKSEpvPYDGDRTLEDFSKFIAKHATFPL 458

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 34784103  86 ELTATNFKSHIAKGSH--FVKFFAPWCGHCKAMAPTWEQLASSFEHSDSIKISKVDCTQ-HYEVCSDNQVRGYPTLLFF- 161
Cdd:cd02998   4 ELTDSNFDKVVGDDKKdvLVEFYAPWCGHCKNLAPEYEKLAAVFANEDDVVIAKVDADEaNKDLAKKYGVSGFPTLKFFp 83

                        90       100
                ....*....|....*....|..
gi 34784103 162 TDGEKIDQYRGKRDLDSFKEFV 183
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 34784103   218 NVLVLTESNFDETVAK--GLSFIKFYAPWCGHCKNLAPTWDDLSQkEFPGltDVKIAKVDCTVERTLCNRFSVRGYPTLL 295
Cdd:pfam00085   1 VVVVLTDANFDEVVQKssKPVLVDFYAPWCGPCKMLAPEYEELAQ-EYKG--NVVFAKVDVDENPDLASKYGVRGYPTLI 77

                          90       100
                  ....*....|....*....|....
gi 34784103   296 MFRAGQQGEEHNGGRDLESLHSFI 319
Cdd:pfam00085  78 FFKNGQPVDDYVGARPKDALAAFL 101

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 34784103 218 NVLVLTESNFDETV--AKGLSFIKFYAPWCGHCKNLAPTWDDLSqKEFPGLtdVKIAKVDCTVERTLCNRFSVRGYPTLL 295
Cdd:cd03001   1 DVVELTDSNFDKKVlnSDDVWLVEFYAPWCGHCKNLAPEWKKAA-KALKGI--VKVGAVDADVHQSLAQQYGVRGFPTIK 77

                        90       100
                ....*....|....*....|....*.
gi 34784103 296 MFRAGQQG-EEHNGGRDLESLHSFIM 320
Cdd:cd03001  78 VFGAGKNSpQDYQGGRTAKAIVSAAL 103

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 34784103  86 ELTATNFKSHIAKGSH--FVKFFAPWCGHCKAMAPTWEQLASsfEHSDSIKISKVDCTQHYEVCSDNQVRGYPTLLFFTD 163
Cdd:COG3118   4 ELTDENFEEEVLESDKpvLVDFWAPWCGPCKMLAPVLEELAA--EYGGKVKFVKVDVDENPELAAQFGVRSIPTLLLFKD 81

                        90       100
                ....*....|....*....|....
gi 34784103 164 GEKIDQYRGKRDLDSFKEFVDNHV 187
Cdd:COG3118  82 GQPVDRFVGALPKEQLREFLDKVL 105

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 34784103 219 VLVLTESNFDETVAKGL--SFIKFYAPWCGHCKNLAPTWDDLSQKeFPGLTDVKIAKVDCT---VErtlcNRFSVRGYPT 293
Cdd:cd02995   2 VKVVVGKNFDEVVLDSDkdVLVEFYAPWCGHCKALAPIYEELAEK-LKGDDNVVIAKMDATandVP----SEFVVDGFPT 76

                        90       100
                ....*....|....*....|....*...
gi 34784103 294 LLMFRAGQQGE--EHNGGRDLESLHSFI 319
Cdd:cd02995  77 ILFFPAGDKSNpiKYEGDRTLEDLIKFI 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 34784103 218 NVLVLTESNFDETV--AKGLSFIKFYAPWCGHCKNLAPTWDDLSqKEFPGltDVKIAKVDCTVERTLCNRFSVRGYPTLL 295
Cdd:COG3118   1 AVVELTDENFEEEVleSDKPVLVDFWAPWCGPCKMLAPVLEELA-AEYGG--KVKFVKVDVDENPELAAQFGVRSIPTLL 77

                        90       100
                ....*....|....*....|....
gi 34784103 296 MFRAGQQGEEHNGGRDLESLHSFI 319
Cdd:COG3118  78 LFKDGQPVDRFVGALPKEQLREFL 101

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 34784103  86 ELTATNFKSHI--AKGSHFVKFFAPWCGHCKAMAPTWEQLASSFEhsDSIKISKVDCTQHYEVCSDNQVRGYPTLLFFTD 163
Cdd:cd03001   4 ELTDSNFDKKVlnSDDVWLVEFYAPWCGHCKNLAPEWKKAAKALK--GIVKVGAVDADVHQSLAQQYGVRGFPTIKVFGA 81

                        90       100
                ....*....|....*....|.
gi 34784103 164 G-EKIDQYRGKRDLDSFKEFV 183
Cdd:cd03001  82 GkNSPQDYQGGRTAKAIVSAA 102

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 34784103 219 VLVLTESNFDETVAKG-LSFIKFYAPWCGHCKNLAPTWDDLSqKEFPGLtdVKIAKVDCTVERTLCNRFSVRGYPTLLMF 297
Cdd:cd03003   3 IVTLDRGDFDAAVNSGeIWFVNFYSPRCSHCHDLAPTWREFA-KEMDGV--IRIGAVNCGDDRMLCRSQGVNSYPSLYVF 79

                        90       100
                ....*....|....*....|.
gi 34784103 298 RAGQQGEEHNGGRDLESLHSF 318
Cdd:cd03003  80 PSGMNPEKYYGDRSKESLVKF 100

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 34784103  91 NFKSHIAK-GSHFVKFFAPWCGHCKAMAPTWEQLAssfEHSDSIKISKVDCTQHYEVCSDNQVRGYPTLLFFTDGEKIDQ 169
Cdd:cd02947   2 EFEELIKSaKPVVVDFWAPWCGPCKAIAPVLEELA---EEYPKVKFVKVDVDENPELAEEYGVRSIPTFLFFKNGKEVDR 78

                        90
                ....*....|....*
gi 34784103 170 YRGKRDLDSFKEFVD 184
Cdd:cd02947  79 VVGADPKEELEEFLE 93

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 34784103    87 LTATNFKSHIAKGSH--FVKFFAPWCGHCKAMAPTWEQLASsfEHSDSIKISKVDCTQHYEVCSDNQVRGYPTLLFFTDG 164
Cdd:TIGR01068   1 LTDANFDETIASSDKpvLVDFWAPWCGPCKMIAPILEELAK--EYEGKVKFVKLNVDENPDIAAKYGIRSIPTLLLFKNG 78

                          90       100
                  ....*....|....*....|...
gi 34784103   165 EKIDQYRGKRDLDSFKEFVDNHV 187
Cdd:TIGR01068  79 KEVDRSVGALPKAALKQLINKNL 101

Thioredoxin domain-containing protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 34784103   84 LYELTATNFK------SHIAKGSHFVKFFAPWCGHCKAMAPTWEQLASSFEhsDSIKISKVDCTQHYEVCSDNQVRGYPT 157
Cdd:PTZ00443  32 LVLLNDKNFEkltqasTGATTGPWFVKFYAPWCSHCRKMAPAWERLAKALK--GQVNVADLDATRALNLAKRFAIKGYPT 109

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 34784103  158 LLFFTDGeKIDQYR-GKRDLDSFKEFVDNHVKAAESKDEPE 197
Cdd:PTZ00443 110 LLLFDKG-KMYQYEgGDRSTEKLAAFALGDFKKALGAPVPA 149

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 34784103  92 FKSHIAKGSHFVKFFAPWCGHCKAMAPTWEQLASSFEHSDS-IKISKVDCTQHYEVCSDNQVRGYPTLLFFTDGEKIDqY 170
Cdd:cd03000   9 FKDVRKEDIWLVDFYAPWCGHCKKLEPVWNEVGAELKSSGSpVRVGKLDATAYSSIASEFGVRGYPTIKLLKGDLAYN-Y 87

                        90
                ....*....|..
gi 34784103 171 RGKRDLDSFKEF 182
Cdd:cd03000  88 RGPRTKDDIVEF 99

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 34784103 217 SNVLVLTESNFDEtVAKGLSFIKFYAPWCGHCKNLAPTWDDLS-QKEFPGltdVKIAKVDCTVERTLCNRFSVRGYPTLL 295
Cdd:cd02994   1 SNVVELTDSNWTL-VLEGEWMIEFYAPWCPACQQLQPEWEEFAdWSDDLG---INVAKVDVTQEPGLSGRFFVTALPTIY 76

                        90       100
                ....*....|....*....|....*....
gi 34784103 296 -----MFRagqqgeEHNGGRDLESLHSFI 319
Cdd:cd02994  77 hakdgVFR------RYQGPRDKEDLISFI 99

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 34784103 218 NVLVLTESNFDETVAKGLSF--IKFYAPWCGHCKNLAPTWDDLSQ--KEFPGLtdVKIAKVDCTVERT--LCNRFSVRGY 291
Cdd:cd02992   2 PVIVLDAASFNSALLGSPSAwlVEFYASWCGHCRAFAPTWKKLARdlRKWRPV--VRVAAVDCADEENvaLCRDFGVTGY 79

                        90
                ....*....|....*..
gi 34784103 292 PTLLMFRA----GQQGE 304
Cdd:cd02992  80 PTLRYFPPfskeATDGL 96

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 34784103 225 SNFDETVAK-GLSFIKFYAPWCGHCKNLAPTWDDLSQKEfpglTDVKIAKVDCTVERTLCNRFSVRGYPTLLMFRAGQQG 303
Cdd:cd02947   1 EEFEELIKSaKPVVVDFWAPWCGPCKAIAPVLEELAEEY----PKVKFVKVDVDENPELAEEYGVRSIPTFLFFKNGKEV 76

                        90
                ....*....|....*.
gi 34784103 304 EEHNGGRDLESLHSFI 319
Cdd:cd02947  77 DRVVGADPKEELEEFL 92

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 34784103 217 SNVLVLTESNFDETV-AKGLSFIKFYAPWCGHCKNLAPTWDDLSQK---EFPGLTDVKIAKVDCTVERTLCNRFSVRGYP 292
Cdd:cd02996   1 SEIVSLTSGNIDDILqSAELVLVNFYADWCRFSQMLHPIFEEAAAKikeEFPDAGKVVWGKVDCDKESDIADRYRINKYP 80

                        90       100
                ....*....|....*....|....*...
gi 34784103 293 TLLMFRAGQQG-EEHNGGRDLESLHSFI 319
Cdd:cd02996  81 TLKLFRNGMMMkREYRGQRSVEALAEFV 108