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 530410557 274 DSEDDGESEAAKQLIQPIAEKIIAKYKAKEEEAPLLFFVAGEDDMTDSLRDYTNLPEAAPLLTILDMSARAKYVMDVEEI 353
Cdd:cd03071   23 DSEDEGESEAAKQLIQPIAEKIIAKYKAKEEEAPLLFFVAGEDDMTDSLRDYTNLPEAAPLLTILDMSARAKYVMDVEEI 102

                         90
                 ....*....|....
gi 530410557 354 TPAIVEAFVNDFLA 367
Cdd:cd03071  103 TPAIVEAFVSDFLA 116

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 530410557  11 EKLVTGGGEEVDVHSLGArgiSLLGLYFGCSLSAPCAQLSASLAAFYGRLRgdaaagpgpgagagaaaepEPRRRLEIVF 90
Cdd:cd03009    1 DFLLRNDGGKVPVSSLEG---KTVGLYFSASWCPPCRAFTPKLVEFYEKLK-------------------ESGKNFEIVF 58

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 530410557  91 VSSDQDQRQWQDFVRDMPWLALPYKEKHRKLKLWNKYRISNIPSLIFLDAtTGKVVCRNGLLVIRdDPEGLEFPW 165
Cdd:cd03009   59 ISWDRDEESFNDYFSKMPWLAVPFSDRERRSRLNRTFKIEGIPTLIILDA-DGEVVTTDARELVL-EYGADAFPF 131

PDIb' family, NRX subgroup, redox inactive TRX-like domain b'; composed of vertebrate nucleoredoxins (NRX). NRX is a 400-amino acid nuclear protein with one redox active TRX domain followed by one redox inactive TRX-like domain homologous to the b' domain of PDI. In vitro studies show that NRX has thiol oxidoreductase activity and that it may be involved in the redox regulation of transcription, in a manner different from that of TRX or glutaredoxin. NRX enhances the activation of NF-kB by TNFalpha, as well as PMA-1 induced AP-1 and FK-induced CREB activation. Mouse NRX transcripts are expressed in all adult tissues but is restricted to the nervous system and limb buds in embryos. The mouse NRX gene is implicated in streptozotocin-induced diabetes. Similar to PDI, the b' domain of NRX is likely involved in substrate recognition.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530410557 274 DSEDDGESEAAKQLIQPIAEKIIAKYKAKEEEAPLLFFVAGEDDMTDSLRDYTNLPEAAPLLTILDMSARAKYVMDVEEI 353
Cdd:cd03071   23 DSEDEGESEAAKQLIQPIAEKIIAKYKAKEEEAPLLFFVAGEDDMTDSLRDYTNLPEAAPLLTILDMSARAKYVMDVEEI 102

                         90
                 ....*....|....
gi 530410557 354 TPAIVEAFVNDFLA 367
Cdd:cd03071  103 TPAIVEAFVSDFLA 116

Tryparedoxin (TryX)-like family, TryX and nucleoredoxin (NRX) subfamily; TryX and NRX are thioredoxin (TRX)-like protein disulfide oxidoreductases that alter the redox state of target proteins via the reversible oxidation of an active center CXXC motif. TryX is involved in the regulation of oxidative stress in parasitic trypanosomatids by reducing TryX peroxidase, which in turn catalyzes the reduction of hydrogen peroxide and organic hydroperoxides. TryX derives reducing equivalents from reduced trypanothione, a polyamine peptide conjugate unique to trypanosomatids, which is regenerated by the NADPH-dependent flavoprotein trypanothione reductase. Vertebrate NRX is a 400-amino acid nuclear protein with one redox active TRX domain containing a CPPC active site motif followed by one redox inactive TRX-like domain. Mouse NRX transcripts are expressed in all adult tissues but is restricted to the nervous system and limb buds in embryos. Plant NRX, longer than the vertebrate NRX by about 100-200 amino acids, is a nuclear protein containing a redox inactive TRX-like domain between two redox active TRX domains. Both vertebrate and plant NRXs show thiol oxidoreductase activity in vitro. Their localization in the nucleus suggests a role in the redox regulation of nuclear proteins such as transcription factors.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530410557  11 EKLVTGGGEEVDVHSLGArgiSLLGLYFGCSLSAPCAQLSASLAAFYGRLRgdaaagpgpgagagaaaepEPRRRLEIVF 90
Cdd:cd03009    1 DFLLRNDGGKVPVSSLEG---KTVGLYFSASWCPPCRAFTPKLVEFYEKLK-------------------ESGKNFEIVF 58

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 530410557  91 VSSDQDQRQWQDFVRDMPWLALPYKEKHRKLKLWNKYRISNIPSLIFLDAtTGKVVCRNGLLVIRdDPEGLEFPW 165
Cdd:cd03009   59 ISWDRDEESFNDYFSKMPWLAVPFSDRERRSRLNRTFKIEGIPTLIILDA-DGEVVTTDARELVL-EYGADAFPF 131

Thioredoxin-like; Thioredoxins are small enzymes that participate in redox reactions, via the reversible oxidation of an active centre disulfide bond.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530410557   33 LLGLYFGCSLSAPCAQLSASLAAFYGRLRGDaaagpgpgagagaaaepeprRRLEIVFVSSDQDQRQWQDFVRDMP--WL 110
Cdd:pfam13905   3 VVLLYFGASWCKPCRRFTPLLKELYEKLKKK--------------------KNVEIVFVSLDRDLEEFKDYLKKMPkdWL 62

                          90       100
                  ....*....|....*....|....*....
gi 530410557  111 ALPYKEKHRKlKLWNKYRISNIPSLIFLD 139
Cdd:pfam13905  63 SVPFDDDERN-ELKRKYGVNAIPTLVLLD 90

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

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 530410557 198 VYFSAHWCPPCRSLTRVLVESYRKIKeagqNFEIIFVSADRSEESFKQYFSEMPWLAVPYTDEarRSRLNRLYGIQ 273
Cdd:COG0526   33 VNFWATWCPPCRAEMPVLKELAEEYG----GVVFVGVDVDENPEAVKAFLKELGLPYPVLLDP--DGELAKAYGVR 102

PDIb' family, NRX subgroup, redox inactive TRX-like domain b'; composed of vertebrate nucleoredoxins (NRX). NRX is a 400-amino acid nuclear protein with one redox active TRX domain followed by one redox inactive TRX-like domain homologous to the b' domain of PDI. In vitro studies show that NRX has thiol oxidoreductase activity and that it may be involved in the redox regulation of transcription, in a manner different from that of TRX or glutaredoxin. NRX enhances the activation of NF-kB by TNFalpha, as well as PMA-1 induced AP-1 and FK-induced CREB activation. Mouse NRX transcripts are expressed in all adult tissues but is restricted to the nervous system and limb buds in embryos. The mouse NRX gene is implicated in streptozotocin-induced diabetes. Similar to PDI, the b' domain of NRX is likely involved in substrate recognition.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530410557 274 DSEDDGESEAAKQLIQPIAEKIIAKYKAKEEEAPLLFFVAGEDDMTDSLRDYTNLPEAAPLLTILDMSARAKYVMDVEEI 353
Cdd:cd03071   23 DSEDEGESEAAKQLIQPIAEKIIAKYKAKEEEAPLLFFVAGEDDMTDSLRDYTNLPEAAPLLTILDMSARAKYVMDVEEI 102

                         90
                 ....*....|....
gi 530410557 354 TPAIVEAFVNDFLA 367
Cdd:cd03071  103 TPAIVEAFVSDFLA 116

Tryparedoxin (TryX)-like family; composed of TryX and related proteins including nucleoredoxin (NRX), rod-derived cone viability factor (RdCVF) and the nematode homolog described as a 16-kD class of TRX. Most members of this family, except RdCVF, are protein disulfide oxidoreductases containing an active site CXXC motif, similar to TRX.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530410557 195 HVGVYFSAHWCPPCRSLTRVLVESYRKIKEAGQNFEIIFVSADRSEESFKQYFSEM-PWLAVPYTDEARRSRLNRLYGIQ 273
Cdd:cd02964   19 TVGLYFSASWCPPCRAFTPKLVEFYEKLKEEGKNFEIVFVSRDRSEESFNEYFSEMpPWLAVPFEDEELRELLEKQFKVE 98

Tryparedoxin (TryX)-like family; composed of TryX and related proteins including nucleoredoxin (NRX), rod-derived cone viability factor (RdCVF) and the nematode homolog described as a 16-kD class of TRX. Most members of this family, except RdCVF, are protein disulfide oxidoreductases containing an active site CXXC motif, similar to TRX.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530410557  17 GGEEVDVHSLGARgisLLGLYFGCSLSAPCAQLSASLAAFYGRLRgdaaagpgpgagagaaaepEPRRRLEIVFVSSDQD 96
Cdd:cd02964    6 GEGVVPVSALEGK---TVGLYFSASWCPPCRAFTPKLVEFYEKLK-------------------EEGKNFEIVFVSRDRS 63

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530410557  97 QRQWQDFVRDM-PWLALPYKEKHRKLKLWNKYRISNIPSLIFLDAtTGKVVCRNGLLVIRDDPEGLEFPW 165
Cdd:cd02964   64 EESFNEYFSEMpPWLAVPFEDEELRELLEKQFKVEGIPTLVVLKP-DGDVVTTNARDEVEEDPGACAFPW 132

Thioredoxin-like; Thioredoxins are small enzymes that participate in redox reactions, via the reversible oxidation of an active centre disulfide bond.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530410557   33 LLGLYFGCSLSAPCAQLSASLAAFYGRLRGDaaagpgpgagagaaaepeprRRLEIVFVSSDQDQRQWQDFVRDMP--WL 110
Cdd:pfam13905   3 VVLLYFGASWCKPCRRFTPLLKELYEKLKKK--------------------KNVEIVFVSLDRDLEEFKDYLKKMPkdWL 62

                          90       100
                  ....*....|....*....|....*....
gi 530410557  111 ALPYKEKHRKlKLWNKYRISNIPSLIFLD 139
Cdd:pfam13905  63 SVPFDDDERN-ELKRKYGVNAIPTLVLLD 90

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 530410557  226 GQNFEIIFVSADRSEESFKQYFSEMpwlAVPYTDEARRSRLNRLYG--------IQDSEDDGESEAAKQLIQPIAEKiia 297
Cdd:TIGR01130 190 DEKFSKVDGEMDTDVSDLEKFIRAE---SLPLVGEFTQETAAKYFEsgplvvlyYNVDESLDPFEELRNRFLEAAKK--- 263

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530410557  298 kYKAKEeeapLLFFVAGEDDMTDSLRDYTNLPEAAPLLTILDMSARAKYVMDVEEITPAIVEAFVNDFLAEKLKP----E 373
Cdd:TIGR01130 264 -FRGKF----VNFAVADEEDFGRELEYFGLKAEKFPAVAIQDLEGNKKYPMDQEEFSSENLEAFVKDFLDGKLKPylksE 338

                  ..
gi 530410557  374 PI 375
Cdd:TIGR01130 339 PI 340

Tryparedoxin (TryX)-like family, Rod-derived cone viability factor (RdCVF) subfamily; RdCVF is a thioredoxin (TRX)-like protein specifically expressed in photoreceptors. RdCVF was isolated and identified as a factor that supports cone survival in retinal cultures. Cone photoreceptor loss is responsible for the visual handicap resulting from the inherited disease, retinitis pigmentosa. RdCVF shows 33% similarity to TRX but does not exhibit any detectable thiol oxidoreductase activity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530410557  33 LLGLYFGCSLSAPCAQLSASLAAFYGRLRGDAAAGPGPgagagaaaepeprrRLEIVFVSSDQDQRQWQDFVRDMP--WL 110
Cdd:cd03008   27 VLLLFFGAVVSPQCQLFAPKLKDFFVRLTDEFYVDRSA--------------QLALVYVSMDQSEQQQESFLKDMPkkWL 92

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 530410557 111 ALPYKEKHRKlKLWNKYRISNIPSLIFLDAtTGKVVCRNG 150
Cdd:cd03008   93 FLPFEDEFRR-ELEAQFSVEELPTVVVLKP-DGDVLAANA 130

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
                 ....*....|....*....|....*....|....*....|....*....
gi 530410557 198 VYFSAHWCPPCRSLTRVLVEsyrkIKEAGQNFEIIFVSADRSEESFKQY 246
Cdd:cd02947   15 VDFWAPWCGPCKAIAPVLEE----LAEEYPKVKFVKVDVDENPELAEEY 59

TlpA-like family; composed of TlpA, ResA, DsbE and similar proteins. TlpA, ResA and DsbE are bacterial protein disulfide reductases with important roles in cytochrome maturation. They are membrane-anchored proteins with a soluble TRX domain containing a CXXC motif located in the periplasm. The TRX domains of this family contain an insert, approximately 25 residues in length, which correspond to an extra alpha helix and a beta strand when compared with TRX. TlpA catalyzes an essential reaction in the biogenesis of cytochrome aa3, while ResA and DsbE are essential proteins in cytochrome c maturation. Also included in this family are proteins containing a TlpA-like TRX domain with domain architectures similar to E. coli DipZ protein, and the N-terminal TRX domain of PilB protein from Neisseria which acts as a disulfide reductase that can recylce methionine sulfoxide reductases.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 530410557 198 VYFSAHWCPPCRSLTRVLVESYRKIKeaGQNFEIIFVSADRSEES-FKQYFSEMPWLAVPYTDEarRSRLNRLYGIQ 273
Cdd:cd02966   24 VNFWASWCPPCRAEMPELEALAKEYK--DDGVEVVGVNVDDDDPAaVKAFLKKYGITFPVLLDP--DGELAKAYGVR 96

Tryparedoxin (TryX)-like family, Rod-derived cone viability factor (RdCVF) subfamily; RdCVF is a thioredoxin (TRX)-like protein specifically expressed in photoreceptors. RdCVF was isolated and identified as a factor that supports cone survival in retinal cultures. Cone photoreceptor loss is responsible for the visual handicap resulting from the inherited disease, retinitis pigmentosa. RdCVF shows 33% similarity to TRX but does not exhibit any detectable thiol oxidoreductase activity.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 530410557 198 VYFSAHWCPPCRSLTRVLVESYRKIK-----EAGQNFEIIFVSADRSEESFKQYFSEMP--WLAVPYTDEARR 263
Cdd:cd03008   30 LFFGAVVSPQCQLFAPKLKDFFVRLTdefyvDRSAQLALVYVSMDQSEQQQESFLKDMPkkWLFLPFEDEFRR 102