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 568977859   1 MVIHHLEDCQYCQALKKEFAKNEEIQEMAQNDFIMLNLMHETTDKNLSPDGQYVPRIMFVDPSLTVRADITGRYSNRLYT 80
Cdd:cd02960   27 MVIHHLEDCPHSQALKKAFAEHKEIQKLAQEDFIMLNLVHETTDKNLSPDGQYVPRIMFVDPSLTVRADITGRYSNRLYT 106

                         90       100
                 ....*....|....*....|....
gi 568977859  81 YEPQDLPMLVDNMKKALRLIQSEL 104
Cdd:cd02960  107 YEPADIPLLIENMKKALKLLKTEL 130

Anterior Gradient (AGR) family; members of this family are similar to secreted proteins encoded by the cement gland-specific genes XAG-1 and XAG-2, expressed in the anterior region of dorsal ectoderm of Xenopus. They are implicated in the formation of the cement gland and the induction of forebrain fate. The human homologs, hAG-2 and hAG-3, are secreted proteins associated with estrogen-positive breast tumors. Yeast two-hybrid studies identified the metastasis-associated C4.4a protein and dystroglycan as binding partners, indicating possible roles in the development and progression of breast cancer. hAG-2 has also been implicated in prostate cancer. Its gene was cloned as an androgen-inducible gene and it was shown to be overexpressed in prostate cancer cells at the mRNA and protein levels. AGR proteins contain one conserved cysteine corresponding to the first cysteine in the CXXC motif of TRX. They show high sequence similarity to ERp19.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568977859   1 MVIHHLEDCQYCQALKKEFAKNEEIQEMAQNDFIMLNLMHETTDKNLSPDGQYVPRIMFVDPSLTVRADITGRYSNRLYT 80
Cdd:cd02960   27 MVIHHLEDCPHSQALKKAFAEHKEIQKLAQEDFIMLNLVHETTDKNLSPDGQYVPRIMFVDPSLTVRADITGRYSNRLYT 106

                         90       100
                 ....*....|....*....|....
gi 568977859  81 YEPQDLPMLVDNMKKALRLIQSEL 104
Cdd:cd02960  107 YEPADIPLLIENMKKALKLLKTEL 130

Thioredoxin-related protein SoxW [Posttranslational modification, protein turnover, chaperones];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568977859   1 MVIHHLEDCQYCQALKKEFAKNEEIQEMAQNDFIMLNLMHETTDKNLSPDGQ--------------YVPRIMFVDPSLTV 66
Cdd:COG2143   44 LLFFESDWCPYCKKLHKEVFSDPEVAAYLKENFVVVQLDAEGDKEVTDFDGEtltekelarkygvrGTPTLVFFDAEGKE 123

                 ....*.
gi 568977859  67 RADITG 72
Cdd:COG2143  124 IARIPG 129

Anterior Gradient (AGR) family; members of this family are similar to secreted proteins encoded by the cement gland-specific genes XAG-1 and XAG-2, expressed in the anterior region of dorsal ectoderm of Xenopus. They are implicated in the formation of the cement gland and the induction of forebrain fate. The human homologs, hAG-2 and hAG-3, are secreted proteins associated with estrogen-positive breast tumors. Yeast two-hybrid studies identified the metastasis-associated C4.4a protein and dystroglycan as binding partners, indicating possible roles in the development and progression of breast cancer. hAG-2 has also been implicated in prostate cancer. Its gene was cloned as an androgen-inducible gene and it was shown to be overexpressed in prostate cancer cells at the mRNA and protein levels. AGR proteins contain one conserved cysteine corresponding to the first cysteine in the CXXC motif of TRX. They show high sequence similarity to ERp19.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568977859   1 MVIHHLEDCQYCQALKKEFAKNEEIQEMAQNDFIMLNLMHETTDKNLSPDGQYVPRIMFVDPSLTVRADITGRYSNRLYT 80
Cdd:cd02960   27 MVIHHLEDCPHSQALKKAFAEHKEIQKLAQEDFIMLNLVHETTDKNLSPDGQYVPRIMFVDPSLTVRADITGRYSNRLYT 106

                         90       100
                 ....*....|....*....|....
gi 568977859  81 YEPQDLPMLVDNMKKALRLIQSEL 104
Cdd:cd02960  107 YEPADIPLLIENMKKALKLLKTEL 130

Endoplasmic reticulum protein 19 (ERp19) family; ERp19 is also known as ERp18, a protein located in the ER containing one redox active TRX domain. Denaturation studies indicate that the reduced form is more stable than the oxidized form, suggesting that the protein is involved in disulfide bond formation. In vitro, ERp19 has been shown to possess thiol-disulfide oxidase activity which is dependent on the presence of both active site cysteines. Although described as protein disulfide isomerase (PDI)-like, the protein does not complement for PDI activity. ERp19 shows a wide tissue distribution but is most abundant in liver, testis, heart and kidney.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568977859   1 MVIHHLEDCQYCQALKKEFAKNEEIQEMAQNdFIMLNLM--HETTDKNLSPDGQYVPRIMFVDPSLTVRADITGRYSNRL 78
Cdd:cd02959   23 MLLIHKTWCGACKALKPKFAESKEISELSHN-FVMVNLEddEEPKDEEFSPDGGYIPRILFLDPSGDVHPEIINKKGNPN 101

                         90
                 ....*....|....*.
gi 568977859  79 YTYEPQDLPMLVDNMK 94
Cdd:cd02959  102 YKYFYSSAAQVTESMK 117