TMX2 family; composed of proteins similar to human TMX2, a 372-amino acid TRX-related transmembrane protein, identified and characterized through the cloning of its cDNA from a human fetal library. It contains a TRX domain but the redox active CXXC motif is replaced with SXXC. Sequence analysis predicts that TMX2 may be a Type I membrane protein, with its C-terminal half protruding on the luminal side of the endoplasmic reticulum (ER). In addition to the TRX domain, transmembrane region and ER-retention signal, TMX2 also contains a Myb DNA-binding domain repeat signature and a dileucine motif in the tail.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1119202221 109 DIRMGLLYITLCIVFLMTCKPPLYMGPEYIKYFNDKTIDEELERDKRVTWIVEFFANWSNDCQSFAPIYADLSLKYNCTG 188
Cdd:cd02962     1 DIRLGLLYLLLCIVVYLLAPQPLYMGPEHIKYFTPKTLEEELERDKRVTWLVEFFTTWSPECVNFAPVFAELSLKYNNNN 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1119202221 189 LNFGKVDVGRYTDVStrelsgpCRYKVSTSPLTKQLPTLILFQGGKEAMRRP-QIDKKGRAVSWTFSEENVIREFNLNE 266
Cdd:cd02962    81 LKFGKIDIGRFPNVA-------EKFRVSTSPLSKQLPTIILFQGGKEVARRPyYNDSKGRAVPFTFSKENVIRHFDLDR 152

TMX2 family; composed of proteins similar to human TMX2, a 372-amino acid TRX-related transmembrane protein, identified and characterized through the cloning of its cDNA from a human fetal library. It contains a TRX domain but the redox active CXXC motif is replaced with SXXC. Sequence analysis predicts that TMX2 may be a Type I membrane protein, with its C-terminal half protruding on the luminal side of the endoplasmic reticulum (ER). In addition to the TRX domain, transmembrane region and ER-retention signal, TMX2 also contains a Myb DNA-binding domain repeat signature and a dileucine motif in the tail.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1119202221 109 DIRMGLLYITLCIVFLMTCKPPLYMGPEYIKYFNDKTIDEELERDKRVTWIVEFFANWSNDCQSFAPIYADLSLKYNCTG 188
Cdd:cd02962     1 DIRLGLLYLLLCIVVYLLAPQPLYMGPEHIKYFTPKTLEEELERDKRVTWLVEFFTTWSPECVNFAPVFAELSLKYNNNN 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1119202221 189 LNFGKVDVGRYTDVStrelsgpCRYKVSTSPLTKQLPTLILFQGGKEAMRRP-QIDKKGRAVSWTFSEENVIREFNLNE 266
Cdd:cd02962    81 LKFGKIDIGRFPNVA-------EKFRVSTSPLSKQLPTIILFQGGKEVARRPyYNDSKGRAVPFTFSKENVIRHFDLDR 152

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 1119202221 137 YIKYFNDKTIDEE-LERDKRVtwIVEFFANWSNDCQSFAPIYADLSLKYNcTGLNFGKVDVGRYtdvstRELSGpcRYKV 215
Cdd:COG3118     1 AVVELTDENFEEEvLESDKPV--LVDFWAPWCGPCKMLAPVLEELAAEYG-GKVKFVKVDVDEN-----PELAA--QFGV 70

                          90       100
                  ....*....|....*....|...
gi 1119202221 216 STspltkqLPTLILFQGGKEAMR 238
Cdd:COG3118    71 RS------IPTLLLFKDGQPVDR 87

Thioredoxin; Thioredoxins are small enzymes that participate in redox reactions, via the reversible oxidation of an active centre disulfide bond. Some members with only the active site are not separated from the noise.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1119202221 138 IKYFNDKTIDEEL-ERDKRVtwIVEFFANWSNDCQSFAPIYADLSLKYNCTgLNFGKVDVgrytdvsTRELSGPCRYKVS 216
Cdd:pfam00085   2 VVVLTDANFDEVVqKSSKPV--LVDFYAPWCGPCKMLAPEYEELAQEYKGN-VVFAKVDV-------DENPDLASKYGVR 71

                          90       100
                  ....*....|....*....|
gi 1119202221 217 TspltkqLPTLILFQGGKEA 236
Cdd:pfam00085  72 G------YPTLIFFKNGQPV 85

TMX2 family; composed of proteins similar to human TMX2, a 372-amino acid TRX-related transmembrane protein, identified and characterized through the cloning of its cDNA from a human fetal library. It contains a TRX domain but the redox active CXXC motif is replaced with SXXC. Sequence analysis predicts that TMX2 may be a Type I membrane protein, with its C-terminal half protruding on the luminal side of the endoplasmic reticulum (ER). In addition to the TRX domain, transmembrane region and ER-retention signal, TMX2 also contains a Myb DNA-binding domain repeat signature and a dileucine motif in the tail.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1119202221 109 DIRMGLLYITLCIVFLMTCKPPLYMGPEYIKYFNDKTIDEELERDKRVTWIVEFFANWSNDCQSFAPIYADLSLKYNCTG 188
Cdd:cd02962     1 DIRLGLLYLLLCIVVYLLAPQPLYMGPEHIKYFTPKTLEEELERDKRVTWLVEFFTTWSPECVNFAPVFAELSLKYNNNN 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1119202221 189 LNFGKVDVGRYTDVStrelsgpCRYKVSTSPLTKQLPTLILFQGGKEAMRRP-QIDKKGRAVSWTFSEENVIREFNLNE 266
Cdd:cd02962    81 LKFGKIDIGRFPNVA-------EKFRVSTSPLSKQLPTIILFQGGKEVARRPyYNDSKGRAVPFTFSKENVIRHFDLDR 152

Protein Disulfide Isomerase (PDIa) family, redox active TRX domains; composed of eukaryotic proteins involved in oxidative protein folding in the endoplasmic reticulum (ER) by acting as catalysts and folding assistants. Members of this family include PDI and PDI-related proteins like ERp72, ERp57 (or ERp60), ERp44, P5, PDIR, ERp46 and the transmembrane PDIs. PDI, ERp57, ERp72, P5, PDIR and ERp46 are all 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. These proteins usually contain multiple copies of a redox active TRX (a) domain containing a CXXC motif, and may also contain one or more redox inactive TRX-like (b) domains. Only one a domain is required for the oxidase function but multiple copies are necessary for the isomerase function. The different types of PDIs may show different substrate specificities and tissue-specific expression, or may be induced by stress. PDIs are in their reduced form at steady state and are oxidized to the active form by Ero1, which is localized in the ER through ERp44. Some members of this family also contain a DnaJ domain in addition to the redox active a domains; examples are ERdj5 and Pfj2. Also included in the family is the redox inactive N-terminal TRX-like domain of ERp29.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1119202221 141 FNDKTIDEELERDKrvTWIVEFFANWSNDCQSFAPIYADLSLKYNCTG-LNFGKVDVGRYTDVSTrelsgpcRYKVstsp 219
Cdd:cd02961     3 LTDDNFDELVKDSK--DVLVEFYAPWCGHCKALAPEYEKLAKELKGDGkVVVAKVDCTANNDLCS-------EYGV---- 69

                          90       100
                  ....*....|....*....|
gi 1119202221 220 ltKQLPTLILFQGGKEAMRR 239
Cdd:cd02961    70 --RGYPTIKLFPNGSKEPVK 87

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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1119202221 144 KTIDEELERDKRVtwIVEFFANWSNDCQSFAPIYADLSLKYNctGLNFGKVDVGRYTDVSTrelsgpcRYKVSTspltkq 223
Cdd:cd02947     1 EEFEELIKSAKPV--VVDFWAPWCGPCKAIAPVLEELAEEYP--KVKFVKVDVDENPELAE-------EYGVRS------ 63

                          90
                  ....*....|....*
gi 1119202221 224 LPTLILFQGGKEAMR 238
Cdd:cd02947    64 IPTFLFFKNGKEVDR 78

thioredoxin 2; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1119202221 127 CKPPLYMGpEYIKYFNDkTIDEELERDKRVtwIVEFFANWSNDCQSFAPIYADLSLKYNctglnfGKVdvgRYTDVST-- 204
Cdd:PRK10996   28 CGHDLFDG-EVINATGE-TLDKLLQDDLPV--VIDFWAPWCGPCRNFAPIFEDVAAERS------GKV---RFVKVNTea 94

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1119202221 205 -RELSGpcRYKVstspltKQLPTLILFQGGK 234
Cdd:PRK10996   95 eRELSA--RFRI------RSIPTIMIFKNGQ 117

Thioredoxin; Thioredoxins are small enzymes that participate in redox reactions, via the reversible oxidation of an active centre disulfide bond. Some members with only the active site are not separated from the noise.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1119202221 138 IKYFNDKTIDEEL-ERDKRVtwIVEFFANWSNDCQSFAPIYADLSLKYNCTgLNFGKVDVgrytdvsTRELSGPCRYKVS 216
Cdd:pfam00085   2 VVVLTDANFDEVVqKSSKPV--LVDFYAPWCGPCKMLAPEYEELAQEYKGN-VVFAKVDV-------DENPDLASKYGVR 71

                          90       100
                  ....*....|....*....|
gi 1119202221 217 TspltkqLPTLILFQGGKEA 236
Cdd:pfam00085  72 G------YPTLIFFKNGQPV 85

PDIa family, TMX subfamily; composed of proteins similar to the TRX-related human transmembrane protein, TMX. TMX is a type I integral membrane protein; the N-terminal redox active TRX domain is present in the endoplasmic reticulum (ER) lumen while the C-terminus is oriented towards the cytoplasm. It is expressed in many cell types and its active site motif (CPAC) is unique. In vitro, TMX reduces interchain disulfides of insulin and renatures inactive RNase containing incorrect disulfide bonds. The C. elegans homolog, DPY-11, is expressed only in the hypodermis and resides in the cytoplasm. It is required for body and sensory organ morphogeneis. Another uncharacterized TRX-related transmembrane protein, human TMX4, is included in the alignment. The active site sequence of TMX4 is CPSC.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1119202221 158 WIVEFFANWSNDCQSFAPIYADLSLKYNCTGLNFGKVDVgrytdvsTRE--LSGpcRYKVSTSP 219
Cdd:cd02994    19 WMIEFYAPWCPACQQLQPEWEEFADWSDDLGINVAKVDV-------TQEpgLSG--RFFVTALP 73

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1119202221 160 VEFFANWSNDCQSFAPIYADLSLKYNC--TGLNFGKVDVGRYTDVSTrelsgpcRYKVstspltKQLPTLILFQGGKEA 236
Cdd:cd03005    21 VKFFAPWCGHCKRLAPTWEQLAKKFNNenPSVKIAKVDCTQHRELCS-------EFQV------RGYPTLLLFKDGEKV 86

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        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1119202221 158 WIVEFFANWSNDCQSFAPIYAD--LSLKYNCTGLNFGKVDVGRYTDVSTrelsgpcRYKVstspltKQLPTLILFQGG 233
Cdd:cd03000    18 WLVDFYAPWCGHCKKLEPVWNEvgAELKSSGSPVRVGKLDATAYSSIAS-------EFGV------RGYPTIKLLKGD 82

Thioredoxin (TRX) superfamily; 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 TRX, protein disulfide isomerase (PDI), tlpA-like, glutaredoxin, NrdH redoxin, and the bacterial Dsb (DsbA, DsbC, DsbG, DsbE, DsbDgamma) protein families. Members of the superfamily that do not function as PDOs but contain a TRX-fold domain include phosducins, peroxiredoxins and 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1119202221 159 IVEFFANWSNDCQSFAPIYADLSLKYncTGLNFGKVDVGRYTDVStrelsgpcryKVSTSPLTKQLPTLILFQGG 233
Cdd:cd01659     1 LVLFYAPWCPFCQALRPVLAELALLN--KGVKFEAVDVDEDPALE----------KELKRYGVGGVPTLVVFGPG 63

PDIa family, Quiescin-sulfhydryl oxidase (QSOX) subfamily; QSOX is a eukaryotic protein containing an N-terminal redox active TRX domain, similar to that of PDI, and a small C-terminal flavin adenine dinucleotide (FAD)-binding domain homologous to the yeast ERV1p protein. QSOX oxidizes thiol groups to disulfides like PDI, however, unlike PDI, this oxidation is accompanied by the reduction of oxygen to hydrogen peroxide. QSOX is localized in high concentrations in cells with heavy secretory load and prefers peptides and proteins as substrates, not monothiols like glutathione. Inside the cell, QSOX is found in the endoplasmic reticulum and Golgi. The flow of reducing equivalents in a QSOX-catalyzed reaction goes from the dithiol substrate -> dithiol of the QSOX TRX domain -> dithiols of the QSOX ERV1p domain -> FAD -> oxygen.

                          10        20
                  ....*....|....*....|....
gi 1119202221 158 WIVEFFANWSNDCQSFAPIYADLS 181
Cdd:cd02992    22 WLVEFYASWCGHCRAFAPTWKKLA 45

thioredoxin TrxA;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1119202221 138 IKYFNDKTIDEELERDKRVTwIVEFFANWSNDCQSFAPIYADLSLKYNctglnfGKVDVGRYtDVSTRELSGPcRYKVst 217
Cdd:PRK09381    5 IIHLTDDSFDTDVLKADGAI-LVDFWAEWCGPCKMIAPILDEIADEYQ------GKLTVAKL-NIDQNPGTAP-KYGI-- 73

                          90       100       110
                  ....*....|....*....|....*....|
gi 1119202221 218 spltKQLPTLILFQGGKEAMRRPQIDKKGR 247
Cdd:PRK09381   74 ----RGIPTLLLFKNGEVAATKVGALSKGQ 99