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        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392899904 118 MIVMFHSPSCPFSARLAPYFNEIAGSYTNILPVAIDASDFTKShrLNFRYGVSGTPTILLwVNGMSVARMSNKKlDLESI 197
Cdd:cd02999   21 TAVLFYASWCPFSASFRPHFNALSSMFPQIRHLAIEESSIKPS--LLSRYGVVGFPTILL-FNSTPRVRYNGTR-TLDSL 96

                 ....
gi 392899904 198 KALI 201
Cdd:cd02999   97 AAFY 100

PDIa family, endoplasmic reticulum protein 44 (ERp44)-like subfamily; composed of uncharacterized PDI-like eukaryotic proteins containing only one redox active TRX (a) domain with a CXXS motif, similar to ERp44. CXXS is still a redox active motif; however, the mixed disulfide formed with the substrate is more stable than those formed by CXXC motif proteins. PDI-related proteins are usually involved in the oxidative protein folding in the ER by acting as catalysts and folding assistants. ERp44 is involved in thiol-mediated retention in the ER.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392899904 118 MIVMFHSPSCPFSARLAPYFNEIAGSYTNILPVAIDASDFTKShrLNFRYGVSGTPTILLwVNGMSVARMSNKKlDLESI 197
Cdd:cd02999   21 TAVLFYASWCPFSASFRPHFNALSSMFPQIRHLAIEESSIKPS--LLSRYGVVGFPTILL-FNSTPRVRYNGTR-TLDSL 96

                 ....
gi 392899904 198 KALI 201
Cdd:cd02999   97 AAFY 100

F plasmid transfer operon protein; TraF protein undergoes proteolytic processing associated with export. The 19 amino acids at the amino terminus of the polypeptides appear to constitute a typical membrane leader peptide - not included in this family, while the remainder of the molecule is predicted to be primarily hydrophilic in character. F plasmid TraF and TraH are required for F pilus assembly and F plasmid transfer, and they are both localized to the outer membrane in the presence of the complete F transfer region, especially TraV, the putative anchor.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392899904  105 LTNLRDTYGrdwcmIVMFHSPSCPFSARLAP---YFNEIAGSYtnILPVAID------ASDFTKSHRLNFRYGVSGTPTI 175
Cdd:pfam13728 124 LKSLAEEFG-----LIFFYRGDCPYCEAQAPilqAFADKYGWT--VRPVSVDgrplpgFPNYRVDNGQAARLGVKRTPAL 196

                  ...
gi 392899904  176 LLW 178
Cdd:pfam13728 197 FLV 199

PDIa family, endoplasmic reticulum protein 44 (ERp44)-like subfamily; composed of uncharacterized PDI-like eukaryotic proteins containing only one redox active TRX (a) domain with a CXXS motif, similar to ERp44. CXXS is still a redox active motif; however, the mixed disulfide formed with the substrate is more stable than those formed by CXXC motif proteins. PDI-related proteins are usually involved in the oxidative protein folding in the ER by acting as catalysts and folding assistants. ERp44 is involved in thiol-mediated retention in the ER.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392899904 118 MIVMFHSPSCPFSARLAPYFNEIAGSYTNILPVAIDASDFTKShrLNFRYGVSGTPTILLwVNGMSVARMSNKKlDLESI 197
Cdd:cd02999   21 TAVLFYASWCPFSASFRPHFNALSSMFPQIRHLAIEESSIKPS--LLSRYGVVGFPTILL-FNSTPRVRYNGTR-TLDSL 96

                 ....
gi 392899904 198 KALI 201
Cdd:cd02999   97 AAFY 100

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 392899904 119 IVMFHSPSCPFSARLAPYFNEIAGSYTNILPVA-IDASDFtksHRLNFRYGVSGTPTILLWVNGMSVARMSNkKLDLESI 197
Cdd:COG3118   22 LVDFWAPWCGPCKMLAPVLEELAAEYGGKVKFVkVDVDEN---PELAAQFGVRSIPTLLLFKDGQPVDRFVG-ALPKEQL 97

                 ....*..
gi 392899904 198 KALIATH 204
Cdd:COG3118   98 REFLDKV 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 392899904 120 VMFHSPSCPFSARLAPYFNEIAGSYTNILP-VAIDASDFTKSHRLNFRYGVSGTPTILLWVNGMSVARMSNKKlDLESIK 198
Cdd:cd03005   21 VKFFAPWCGHCKRLAPTWEQLAKKFNNENPsVKIAKVDCTQHRELCSEFQVRGYPTLLLFKDGEKVDKYKGTR-DLDSLK 99

                 ...
gi 392899904 199 ALI 201
Cdd:cd03005  100 EFV 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 392899904  93 SVVSMNSSSFLELTnLRDTYGrdwcMIVMFHSPSCPFSARLAPYFNEIAGSYTNILPVAIDASDFTKSHR-LNFRYGVSG 171
Cdd:cd02998    1 NVVELTDSNFDKVV-GDDKKD----VLVEFYAPWCGHCKNLAPEYEKLAAVFANEDDVVIAKVDADEANKdLAKKYGVSG 75

                 ....*
gi 392899904 172 TPTIL 176
Cdd:cd02998   76 FPTLK 80

F plasmid transfer operon protein; TraF protein undergoes proteolytic processing associated with export. The 19 amino acids at the amino terminus of the polypeptides appear to constitute a typical membrane leader peptide - not included in this family, while the remainder of the molecule is predicted to be primarily hydrophilic in character. F plasmid TraF and TraH are required for F pilus assembly and F plasmid transfer, and they are both localized to the outer membrane in the presence of the complete F transfer region, especially TraV, the putative anchor.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392899904  105 LTNLRDTYGrdwcmIVMFHSPSCPFSARLAP---YFNEIAGSYtnILPVAID------ASDFTKSHRLNFRYGVSGTPTI 175
Cdd:pfam13728 124 LKSLAEEFG-----LIFFYRGDCPYCEAQAPilqAFADKYGWT--VRPVSVDgrplpgFPNYRVDNGQAARLGVKRTPAL 196

                  ...
gi 392899904  176 LLW 178
Cdd:pfam13728 197 FLV 199

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 392899904 119 IVMFHSPSCPFSARLAPYFNEIAGSYTNI-LPVAIDASDFTKSHRLNFRYGVSGTPTILLWVNGMS 183
Cdd:cd03000   19 LVDFYAPWCGHCKKLEPVWNEVGAELKSSgSPVRVGKLDATAYSSIASEFGVRGYPTIKLLKGDLA 84

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 392899904 118 MIVMFHSPSCPFSARLAPYFNEIAGSYTNILPVAIDASDFTKSH--RLNFRYGVSGTPTILLWVNG 181
Cdd:cd02997   20 VLVMFYAPWCGHCKKMKPEFTKAATELKEDGKGVLAAVDCTKPEhdALKEEYNVKGFPTFKYFENG 85

Thiol-disulfide isomerase or thioredoxin [Posttranslational modification, protein turnover, chaperones];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392899904 119 IVMFHSPSCPFSARLAPYFNEIAGSYTN--ILPVAID-----ASDFTKSHRLNF------------RYGVSGTP-TILLW 178
Cdd:COG0526   32 LVNFWATWCPPCRAEMPVLKELAEEYGGvvFVGVDVDenpeaVKAFLKELGLPYpvlldpdgelakAYGVRGIPtTVLID 111

                         90       100
                 ....*....|....*....|....*.
gi 392899904 179 VNGMSVARMSNkKLDLESIKALIATH 204
Cdd:COG0526  112 KDGKIVARHVG-PLSPEELEEALEKL 136

PDIa family, C-terminal TRX domain (a') subfamily; composed of the C-terminal redox active a' domains of PDI, ERp72, ERp57 (or ERp60) and EFP1. PDI, ERp72 and ERp57 are endoplasmic reticulum (ER)-resident eukaryotic proteins involved in oxidative protein folding. They are oxidases, catalyzing the formation of disulfide bonds of newly synthesized polypeptides in the ER. They also exhibit reductase activity in acting as isomerases to correct any non-native disulfide bonds, as well as chaperone activity to prevent protein aggregation and facilitate the folding of newly synthesized proteins. PDI and ERp57 have the abb'a' domain structure (where a and a' are redox active TRX domains while b and b' are redox inactive TRX-like domains). PDI also contains an acidic region (c domain) after the a' domain that is absent in ERp57. ERp72 has an additional a domain at the N-terminus (a"abb'a' domain structure). ERp57 interacts with the lectin chaperones, calnexin and calreticulin, and specifically promotes the oxidative folding of glycoproteins, while PDI shows a wider substrate specificity. ERp72 associates with several ER chaperones and folding factors to form complexes in the ER that bind nascent proteins. EFP1 is a binding partner protein of thyroid oxidase, which is responsible for the generation of hydrogen peroxide, a crucial substrate of thyroperoxidase, which functions to iodinate thyroglobulin and synthesize thyroid hormones.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 392899904 118 MIVMFHSPSCPFSARLAPYFNEIA---GSYTNILPVAIDAS--DFTKShrlnfrYGVSGTPTILLW 178
Cdd:cd02995   21 VLVEFYAPWCGHCKALAPIYEELAeklKGDDNVVIAKMDATanDVPSE------FVVDGFPTILFF 80

Peroxiredoxin [Posttranslational modification, protein turnover, chaperones];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392899904 108 LRDTYGRDWC--------MIVMFHSPSCPFSARLAPYFNEIAGSYTN----ILPVAIDASD----FTKSHRLNF------ 165
Cdd:COG1225    6 LPDLDGKTVSlsdlrgkpVVLYFYATWCPGCTAELPELRDLYEEFKDkgveVLGVSSDSDEahkkFAEKYGLPFpllsdp 85

                         90
                 ....*....|....*...
gi 392899904 166 ------RYGVSGTPTILL 177
Cdd:COG1225   86 dgevakAYGVRGTPTTFL 103

thioredoxin; Provisional

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 392899904 118 MIVMFHSPSCPFSARLAPYFNEIAGSYTNILPVAIDASDFTKshrLNFRYGVSGTPTILLWVNGMSV 184
Cdd:PTZ00051  21 VIVDFYAEWCGPCKRIAPFYEECSKEYTKMVFVKVDVDELSE---VAEKENITSMPTFKVFKNGSVV 84