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 1831513700  22 MIVMFHSPSCPFSARLAPYFNEIAGSYTNILPVAIDASDFTKShrLNFRYGVSGTPTILLwVNGMSVARMSNKKlDLESI 101
Cdd:cd02999    21 TAVLFYASWCPFSASFRPHFNALSSMFPQIRHLAIEESSIKPS--LLSRYGVVGFPTILL-FNSTPRVRYNGTR-TLDSL 96

                  ....
gi 1831513700 102 KALI 105
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 1831513700  22 MIVMFHSPSCPFSARLAPYFNEIAGSYTNILPVAIDASDFTKShrLNFRYGVSGTPTILLwVNGMSVARMSNKKlDLESI 101
Cdd:cd02999    21 TAVLFYASWCPFSASFRPHFNALSSMFPQIRHLAIEESSIKPS--LLSRYGVVGFPTILL-FNSTPRVRYNGTR-TLDSL 96

                  ....
gi 1831513700 102 KALI 105
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 1831513700   9 LTNLRDTYGrdwcmIVMFHSPSCPFSARLAP---YFNEIAGSYtnILPVAID------ASDFTKSHRLNFRYGVSGTPTI 79
Cdd:pfam13728 124 LKSLAEEFG-----LIFFYRGDCPYCEAQAPilqAFADKYGWT--VRPVSVDgrplpgFPNYRVDNGQAARLGVKRTPAL 196

                  ...
gi 1831513700  80 LLW 82
Cdd:pfam13728 197 FLV 199

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 1831513700  23 IVMFHSPSCPFSARLAPYFNEIAGSYTN---ILPVAIDasdftKSHRLNFRYGVSGTPTILLWVNGMSVARmSNKKLDLE 99
Cdd:TIGR01068  18 LVDFWAPWCGPCKMIAPILEELAKEYEGkvkFVKLNVD-----ENPDIAAKYGIRSIPTLLLFKNGKEVDR-SVGALPKA 91

                  ....*....
gi 1831513700 100 SIKALIATH 108
Cdd:TIGR01068  92 ALKQLINKN 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 1831513700  22 MIVMFHSPSCPFSARLAPYFNEIAGSYTNILPVAIDASDFTKShrLNFRYGVSGTPTILLwVNGMSVARMSNKKlDLESI 101
Cdd:cd02999    21 TAVLFYASWCPFSASFRPHFNALSSMFPQIRHLAIEESSIKPS--LLSRYGVVGFPTILL-FNSTPRVRYNGTR-TLDSL 96

                  ....
gi 1831513700 102 KALI 105
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 1831513700  23 IVMFHSPSCPFSARLAPYFNEIAGSYTNILPVA-IDASDFtksHRLNFRYGVSGTPTILLWVNGMSVARMSNkKLDLESI 101
Cdd:COG3118    22 LVDFWAPWCGPCKMLAPVLEELAAEYGGKVKFVkVDVDEN---PELAAQFGVRSIPTLLLFKDGQPVDRFVG-ALPKEQL 97

                  ....*..
gi 1831513700 102 KALIATH 108
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 1831513700  24 VMFHSPSCPFSARLAPYFNEIAGSYTNILP-VAIDASDFTKSHRLNFRYGVSGTPTILLWVNGMSVARMSNKKlDLESIK 102
Cdd:cd03005    21 VKFFAPWCGHCKRLAPTWEQLAKKFNNENPsVKIAKVDCTQHRELCSEFQVRGYPTLLLFKDGEKVDKYKGTR-DLDSLK 99

                  ...
gi 1831513700 103 ALI 105
Cdd:cd03005   100 EFV 102

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 1831513700   9 LTNLRDTYGrdwcmIVMFHSPSCPFSARLAP---YFNEIAGSYtnILPVAID------ASDFTKSHRLNFRYGVSGTPTI 79
Cdd:pfam13728 124 LKSLAEEFG-----LIFFYRGDCPYCEAQAPilqAFADKYGWT--VRPVSVDgrplpgFPNYRVDNGQAARLGVKRTPAL 196

                  ...
gi 1831513700  80 LLW 82
Cdd:pfam13728 197 FLV 199

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1831513700  23 IVMFHSPSCPFSARLAPYFNEIAGSYTNILPV-AIDAsdfTKSHRLNFRYGVSGTPTILLWVNGMS 87
Cdd:cd03001    22 LVEFYAPWCGHCKNLAPEWKKAAKALKGIVKVgAVDA---DVHQSLAQQYGVRGFPTIKVFGAGKN 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 1831513700  22 MIVMFHSPSCPFSARLAPYFNEIAGSYTNILPVAIDASDFTKSH--RLNFRYGVSGTPTILLWVNG 85
Cdd:cd02997    20 VLVMFYAPWCGHCKKMKPEFTKAATELKEDGKGVLAAVDCTKPEhdALKEEYNVKGFPTFKYFENG 85

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 1831513700   7 LELTNLRDTYGRDWCMIVMFHSPSCPFSARLAPYFNEIAGSYTNILP----VAIDASDFTKSHRLNFRYGVSGTPTILLW 82
Cdd:cd02996     6 LTSGNIDDILQSAELVLVNFYADWCRFSQMLHPIFEEAAAKIKEEFPdagkVVWGKVDCDKESDIADRYRINKYPTLKLF 85

                  ....*...
gi 1831513700  83 VNGMSVAR 90
Cdd:cd02996    86 RNGMMMKR 93

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831513700  23 IVMFHSPSCPFSARLAPYFNEIAGSYTN--ILPVAID-----ASDFTKSHRLNF------------RYGVSGTP-TILLW 82
Cdd:COG0526    32 LVNFWATWCPPCRAEMPVLKELAEEYGGvvFVGVDVDenpeaVKAFLKELGLPYpvlldpdgelakAYGVRGIPtTVLID 111

                          90       100
                  ....*....|....*....|....*.
gi 1831513700  83 VNGMSVARMSNkKLDLESIKALIATH 108
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 1831513700  22 MIVMFHSPSCPFSARLAPYFNEIA---GSYTNILPVAIDAS--DFTKShrlnfrYGVSGTPTILLW 82
Cdd:cd02995    21 VLVEFYAPWCGHCKALAPIYEELAeklKGDDNVVIAKMDATanDVPSE------FVVDGFPTILFF 80

Peroxiredoxin [Posttranslational modification, protein turnover, chaperones];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831513700  12 LRDTYGRDWC--------MIVMFHSPSCPFSARLAPYFNEIAGSYTN----ILPVAIDASD----FTKSHRLNF------ 69
Cdd:COG1225     6 LPDLDGKTVSlsdlrgkpVVLYFYATWCPGCTAELPELRDLYEEFKDkgveVLGVSSDSDEahkkFAEKYGLPFpllsdp 85

                          90
                  ....*....|....*...
gi 1831513700  70 ------RYGVSGTPTILL 81
Cdd:COG1225    86 dgevakAYGVRGTPTTFL 103

thioredoxin; Provisional

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1831513700  22 MIVMFHSPSCPFSARLAPYFNEIAGSYTNILPVAIDASDFTKshrLNFRYGVSGTPTILLWVNGMSV 88
Cdd:PTZ00051   21 VIVDFYAEWCGPCKRIAPFYEECSKEYTKMVFVKVDVDELSE---VAEKENITSMPTFKVFKNGSVV 84

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831513700  22 MIVMFHSPSCPFSARLAPYFNEIAGSYTNILPVAIDASDFTKSHRLNFRYGVSGTPTILL 81
Cdd:cd03002    21 TLVEFYAPWCGHCKNLKPEYAKAAKELDGLVQVAAVDCDEDKNKPLCGKYGVQGFPTLKV 80