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 7106077   18 KNETLFVAYLASVDPrTKQPWCPTVRAALPLFNNAF-NSSKKLNVVHVYVGNMPQWKTPHNEFRVKFGI-SAVPTLGKYT 95
Cdd:cd02952  20 EGKPIFILFYGDKDP-DGQSWCPDCVKAEPVVREALkAAPEDCVFIYCDVGDRPYWRDPNNPFRTDPKLtTGVPTLLRWK 98

                        90       100
                ....*....|....*....|.
gi 7106077   96 RdaqgnlkTSLLVDYDCLDAN 116
Cdd:cd02952  99 T-------PQRLVEDECLQAD 112

Human TRX-related protein 14 (TRP14)-like family; composed of proteins similar to TRP14, a 14kD cytosolic protein that shows disulfide reductase activity in vitro with a different substrate specificity compared with another human cytosolic protein, TRX1. TRP14 catalyzes the reduction of small disulfide-containing peptides but does not reduce disulfides of ribonucleotide reductase, peroxiredoxin and methionine sulfoxide reductase, which are TRX1 substrates. TRP14 also plays a role in tumor necrosis factor (TNF)-alpha signaling pathways, distinct from that of TRX1. Its depletion promoted TNF-alpha induced activation of c-Jun N-terminal kinase and mitogen-activated protein kinases.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 7106077   18 KNETLFVAYLASVDPrTKQPWCPTVRAALPLFNNAF-NSSKKLNVVHVYVGNMPQWKTPHNEFRVKFGI-SAVPTLGKYT 95
Cdd:cd02952  20 EGKPIFILFYGDKDP-DGQSWCPDCVKAEPVVREALkAAPEDCVFIYCDVGDRPYWRDPNNPFRTDPKLtTGVPTLLRWK 98

                        90       100
                ....*....|....*....|.
gi 7106077   96 RdaqgnlkTSLLVDYDCLDAN 116
Cdd:cd02952  99 T-------PQRLVEDECLQAD 112

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

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 7106077   37 PWCPTVRAALPLFNNAFNSSKKLNVVHVYVG---------------NMPQWKTPHNEFRVKFGISAVPTL 91
Cdd:COG0526  38 TWCPPCRAEMPVLKELAEEYGGVVFVGVDVDenpeavkaflkelglPYPVLLDPDGELAKAYGVRGIPTT 107

Human TRX-related protein 14 (TRP14)-like family; composed of proteins similar to TRP14, a 14kD cytosolic protein that shows disulfide reductase activity in vitro with a different substrate specificity compared with another human cytosolic protein, TRX1. TRP14 catalyzes the reduction of small disulfide-containing peptides but does not reduce disulfides of ribonucleotide reductase, peroxiredoxin and methionine sulfoxide reductase, which are TRX1 substrates. TRP14 also plays a role in tumor necrosis factor (TNF)-alpha signaling pathways, distinct from that of TRX1. Its depletion promoted TNF-alpha induced activation of c-Jun N-terminal kinase and mitogen-activated protein kinases.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 7106077   18 KNETLFVAYLASVDPrTKQPWCPTVRAALPLFNNAF-NSSKKLNVVHVYVGNMPQWKTPHNEFRVKFGI-SAVPTLGKYT 95
Cdd:cd02952  20 EGKPIFILFYGDKDP-DGQSWCPDCVKAEPVVREALkAAPEDCVFIYCDVGDRPYWRDPNNPFRTDPKLtTGVPTLLRWK 98

                        90       100
                ....*....|....*....|.
gi 7106077   96 RdaqgnlkTSLLVDYDCLDAN 116
Cdd:cd02952  99 T-------PQRLVEDECLQAD 112

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
                ....*....|....*....|....*....|....*....|....*....|....*
gi 7106077   37 PWCPTVRAALPLFNNAFNSSKKLNVVHVYVGNMPqwktphnEFRVKFGISAVPTL 91
Cdd:cd02947  20 PWCGPCKAIAPVLEELAEEYPKVKFVKVDVDENP-------ELAEEYGVRSIPTF 67