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 503795763  36 HPVNLSNSRFPGYIQKNELPVLVDFWAPWCGPCRTMAPQFEQAGRAMRGRVLFAKVNTEDEQQIGGRFQIRSIPTMVLFK 115
Cdd:COG3118    1 AVVELTDENFEEEVLESDKPVLVDFWAPWCGPCKMLAPVLEELAAEYGGKVKFVKVDVDENPELAAQFGVRSIPTLLLFK 80

                         90       100
                 ....*....|....*....|..
gi 503795763 116 AGKELARVSGAMGAAELQRWLA 137
Cdd:COG3118   81 DGQPVDRFVGALPKEQLREFLD 102

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 503795763  51 KNELPVLVDFWAPWCGPCRTMAPQFEQAgRAMRGRVLFAKVNTEDEQQIGGRFQIRSIPTMVLFKAGKELARVSGAMGAA 130
Cdd:cd02947    8 KSAKPVVVDFWAPWCGPCKAIAPVLEEL-AEEYPKVKFVKVDVDENPELAEEYGVRSIPTFLFFKNGKEVDRVVGADPKE 86

                 ....*..
gi 503795763 131 ELQRWLA 137
Cdd:cd02947   87 ELEEFLE 93

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 503795763  36 HPVNLSNSRFPGYIQKNELPVLVDFWAPWCGPCRTMAPQFEQAGRAMRGRVLFAKVNTEDEQQIGGRFQIRSIPTMVLFK 115
Cdd:COG3118    1 AVVELTDENFEEEVLESDKPVLVDFWAPWCGPCKMLAPVLEELAAEYGGKVKFVKVDVDENPELAAQFGVRSIPTLLLFK 80

                         90       100
                 ....*....|....*....|..
gi 503795763 116 AGKELARVSGAMGAAELQRWLA 137
Cdd:COG3118   81 DGQPVDRFVGALPKEQLREFLD 102

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 503795763  51 KNELPVLVDFWAPWCGPCRTMAPQFEQAgRAMRGRVLFAKVNTEDEQQIGGRFQIRSIPTMVLFKAGKELARVSGAMGAA 130
Cdd:cd02947    8 KSAKPVVVDFWAPWCGPCKAIAPVLEEL-AEEYPKVKFVKVDVDENPELAEEYGVRSIPTFLFFKNGKEVDRVVGADPKE 86

                 ....*..
gi 503795763 131 ELQRWLA 137
Cdd:cd02947   87 ELEEFLE 93

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 503795763  38 VNLSNSRFPGYIQKNElPVLVDFWAPWCGPCRTMAPQFEQAGRAMR--GRVLFAKVNTEDEQQIGGRFQIRSIPTMVLFK 115
Cdd:cd02961    1 VELTDDNFDELVKDSK-DVLVEFYAPWCGHCKALAPEYEKLAKELKgdGKVVVAKVDCTANNDLCSEYGVRGYPTIKLFP 79

                         90       100
                 ....*....|....*....|..
gi 503795763 116 AGKELARV-SGAMGAAELQRWL 136
Cdd:cd02961   80 NGSKEPVKyEGPRTLESLVEFI 101

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 503795763  55 PVLVDFWAPWCGPCRTMAPQFEQAGRAMRGrVLFAKVNTED----------------------EQQIGGRFQIRSIPTMV 112
Cdd:COG0526   30 PVLVNFWATWCPPCRAEMPVLKELAEEYGG-VVFVGVDVDEnpeavkaflkelglpypvlldpDGELAKAYGVRGIPTTV 108

                         90       100
                 ....*....|....*....|....*.
gi 503795763 113 LF-KAGKELARVSGAMGAAELQRWLA 137
Cdd:COG0526  109 LIdKDGKIVARHVGPLSPEELEEALE 134

thioredoxin TrxA;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 503795763  38 VNLSNSRFPGYIQKNELPVLVDFWAPWCGPCRTMAPQFEQAGRAMRGRVLFAKVNTEDEQQIGGRFQIRSIPTMVLFKAG 117
Cdd:PRK09381   6 IHLTDDSFDTDVLKADGAILVDFWAEWCGPCKMIAPILDEIADEYQGKLTVAKLNIDQNPGTAPKYGIRGIPTLLLFKNG 85

                         90
                 ....*....|....*....
gi 503795763 118 KELARVSGAMGAAELQRWL 136
Cdd:PRK09381  86 EVAATKVGALSKGQLKEFL 104

TRX domain, PICOT (for PKC-interacting cousin of TRX) subfamily; PICOT is a protein that interacts with protein kinase C (PKC) theta, a calcium independent PKC isoform selectively expressed in skeletal muscle and T lymphocytes. PICOT contains an N-terminal TRX-like domain, which does not contain the catalytic CXXC motif, followed by one to three glutaredoxin domains. The TRX-like domain is required for interaction with PKC theta. PICOT inhibits the activation of c-Jun N-terminal kinase and the transcription factors, AP-1 and NF-kB, induced by PKC theta or T-cell activating stimuli.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 503795763  41 SNSRFPGYIQKNEL-PVLVDFWAPWCGPCRTMAPQFEQAGRAMRGRVLFAKVNTEDEQQIGGRFQIRSIPTMVLFKAGKE 119
Cdd:cd02984    1 SEEEFEELLKSDASkLLVLHFWAPWAEPCKQMNQVFEELAKEAFPSVLFLSIEAEELPEISEKFEITAVPTFVFFRNGTI 80

                 ....*..
gi 503795763 120 LARVSGA 126
Cdd:cd02984   81 VDRVSGA 87

PDIa family, C-terminal ERdj5 subfamily; ERdj5, also known as JPDI and macrothioredoxin, is a protein containing an N-terminal DnaJ domain and four redox active TRX domains. This subfamily is composed of the three TRX domains located at the C-terminal half of the protein. ERdj5 is a ubiquitous protein localized in the endoplasmic reticulum (ER) and is abundant in secretory cells. It's transcription is induced during ER stress. It interacts with BiP through its DnaJ domain in an ATP-dependent manner. BiP, an ER-resident member of the Hsp70 chaperone family, functions in ER-associated degradation and protein translocation. Also included in the alignment is the single complete TRX domain of an uncharacterized protein from Tetraodon nigroviridis, which also contains a DnaJ domain at its N-terminus.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 503795763  36 HPVNLSNSRFPGYIQKNELPVLVDFWAPWCGPCRTMAPQFEQAGRAMRGRVLFAKVNTEDEQQIGGRFQIRSIPTMVLFK 115
Cdd:cd03004    2 SVITLTPEDFPELVLNRKEPWLVDFYAPWCGPCQALLPELRKAARALKGKVKVGSVDCQKYESLCQQANIRAYPTIRLYP 81

                 ...
gi 503795763 116 AGK 118
Cdd:cd03004   82 GNA 84

PDIa family, endoplasmic reticulum protein 38 (ERp38) subfamily; composed of proteins similar to the P5-like protein first isolated from alfalfa, which contains two redox active TRX (a) domains at the N-terminus, like human P5, and a C-terminal domain with homology to the C-terminal domain of ERp29, unlike human P5. The cDNA clone of this protein (named G1) was isolated from an alfalfa cDNA library by screening with human protein disulfide isomerase (PDI) cDNA. The G1 protein is constitutively expressed in all major organs of the plant and its expression is induced by treatment with tunicamycin, indicating that it may be a glucose-regulated protein. The G1 homolog in the eukaryotic social amoeba Dictyostelium discoideum is also described as a P5-like protein, which is located in the endoplasmic reticulum (ER) despite the absence of an ER-retrieval signal. G1 homologs from Aspergillus niger and Neurospora crassa have also been characterized, and are named TIGA and ERp38, respectively. Also included in the alignment is an atypical PDI from Leishmania donovani containing a single a domain, and the C-terminal a domain of a P5-like protein from Entamoeba histolytica.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 503795763  38 VNLSNSRFPGYIQKNELPVLVDFWAPWCGPCRTMAPQFEQAGRAMRGR--VLFAKVN-TEDEQQIGGRFQIRSIPTMVLF 114
Cdd:cd02998    3 VELTDSNFDKVVGDDKKDVLVEFYAPWCGHCKNLAPEYEKLAAVFANEddVVIAKVDaDEANKDLAKKYGVSGFPTLKFF 82

                 ....*
gi 503795763 115 KAGKE 119
Cdd:cd02998   83 PKGST 87

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 503795763   35 EHPVNLSNSRFPGYIQKNELpVLVDFWAPWCGPCRTMAPQFEQAGRAMRGR---VLFAKVNTEDEQQIGGRFQIRSIPTM 111
Cdd:TIGR01130   1 EDVLVLTKDNFDDFIKSHEF-VLVEFYAPWCGHCKSLAPEYEKAADELKKKgppIKLAKVDATEEKDLAQKYGVSGYPTL 79

                  ....*..
gi 503795763  112 VLFKAGK 118
Cdd:TIGR01130  80 KIFRNGE 86

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        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 503795763  38 VNLSNSRFPGYIQKNElPVLVDFWAPWCGPCRTMAPQFEQAGRAMR--GRVLFAKVN-TEDEQQ-IGGRFQIRSIPTMVL 113
Cdd:cd02997    3 VHLTDEDFRKFLKKEK-HVLVMFYAPWCGHCKKMKPEFTKAATELKedGKGVLAAVDcTKPEHDaLKEEYNVKGFPTFKY 81

                         90       100
                 ....*....|....*....|...
gi 503795763 114 FKAGKELARVSGAMGAAELQRWL 136
Cdd:cd02997   82 FENGKFVEKYEGERTAEDIIEFM 104

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 503795763  56 VLVDFWAPWCGPCRTMAPQFEQAGRAMRGR--VLFAKVN-TEDEqqIGGRFQIRSIPTMVLFKAGK 118
Cdd:cd02995   21 VLVEFYAPWCGHCKALAPIYEELAEKLKGDdnVVIAKMDaTAND--VPSEFVVDGFPTILFFPAGD 84

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 503795763  49 IQKNELPVLVDFWAPWCGPCRTM------APQFEQagrAMRGRVLFAKVN-------------TEDEQQIGGRFQIRSIP 109
Cdd:COG2143   36 AKAEGKPILLFFESDWCPYCKKLhkevfsDPEVAA---YLKENFVVVQLDaegdkevtdfdgeTLTEKELARKYGVRGTP 112

                         90       100
                 ....*....|....*....|....*...
gi 503795763 110 TMVLFKA-GKELARVSGAMGAAELQRWL 136
Cdd:COG2143  113 TLVFFDAeGKEIARIPGYLKPETFLALL 140

Thioredoxin-like domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 503795763   51 KNELPVLVDFWAPWCGPCRTMA--------------PQFEQAGRAMRGR--VLFAKVNTEDEQQIGGRFQIRSIPTMVLF 114
Cdd:pfam13098   2 GNGKPVLVVFTDPDCPYCKKLKkelledpdvtvylgPNFVFIAVNIWCAkeVAKAFTDILENKELGRKYGVRGTPTIVFF 81

                          90       100
                  ....*....|....*....|..
gi 503795763  115 KAGKELARVSGAMGAAELQRWL 136
Cdd:pfam13098  82 DGKGELLRLPGYVPAEEFLALL 103

disulphide isomerase; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 503795763  45 FPGYIQKNELPVLVDFWAPWCGPCRTMAPQFEQAGRAMR--GRVLFAKVN-TEDEQQIGGrFQIRSIPTMVLFKAG 117
Cdd:PTZ00102 367 FEEIVFKSDKDVLLEIYAPWCGHCKNLEPVYNELGEKYKdnDSIIVAKMNgTANETPLEE-FSWSAFPTILFVKAG 441

TlpA-like family, suppressor for copper sensitivity D protein (ScsD) and actinobacterial DsbE homolog subfamily; composed of ScsD, the DsbE homolog of Mycobacterium tuberculosis (MtbDsbE) and similar proteins, all containing a redox-active CXXC motif. The Salmonella typhimurium ScsD is a thioredoxin-like protein which confers copper tolerance to copper-sensitive mutants of E. coli. MtbDsbE has been characterized as an oxidase in vitro, catalyzing the disulfide bond formation of substrates like hirudin. The reduced form of MtbDsbE is more stable than its oxidized form, consistent with an oxidase function. This is in contrast to the function of DsbE from gram-negative bacteria which is a specific reductase of apocytochrome c.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 503795763  55 PVLVDFWAPWCGPCRTMAPQFEQAGR-------AMR----GRVL---------FAKVNtEDEQQIGGRFQIRSIPTMVLF 114
Cdd:cd03011   22 PVLVYFWATWCPVCRFTSPTVNQLAAdypvvsvALRsgddGAVArfmqkkgygFPVIN-DPDGVISARWGVSVTPAIVIV 100

                         90
                 ....*....|...
gi 503795763 115 KAGKELARVSGAM 127
Cdd:cd03011  101 DPGGIVFVTTGVT 113

Thiol:disulfide interchange protein DsbD [Posttranslational modification, protein turnover, chaperones];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 503795763  55 PVLVDFWAPWCGPCRTM------APQFEQagrAMRGRVLFAKV----NTEDEQQIGGRFQIRSIPTMVLFKA-GKELARV 123
Cdd:COG4232  322 PVFVDFTADWCVTCKENertvfsDPEVQA---ALADDVVLLKAdvtdNDPEITALLKRFGRFGVPTYVFYDPdGEELPRL 398

                         90
                 ....*....|....
gi 503795763 124 SGAMGAAELQRWLA 137
Cdd:COG4232  399 GFMLTADEFLAALE 412

TRX-like protein A (TxlA) family; TxlA was originally isolated from the cyanobacterium Synechococcus. It is found only in oxygenic photosynthetic organisms. TRX is a small enzyme that participate in redox reactions, via the reversible oxidation of an active site dithiol present in a CXXC motif. Disruption of the txlA gene suggests that the protein is involved in the redox regulation of the structure and function of photosynthetic apparatus. The plant homolog (designated as HCF164) is localized in the chloroplast and is involved in the assembly of the cytochrome b6f complex, which takes a central position in photosynthetic electron transport.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 503795763  52 NELPVLVDFWAPWCGPCRTMAPQFEQAGRAMRGRVLFAKVNTEDE--QQIGGRFQIRSIPTMVLF-KAGKELARVSG 125
Cdd:cd02950   19 NGKPTLVEFYADWCTVCQEMAPDVAKLKQKYGDQVNFVMLNVDNPkwLPEIDRYRVDGIPHFVFLdREGNEEGQSIG 95

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 503795763   50 QKNELPVLVDFWAPWCGPCRTMAPQFEQ---AGRAMRGRVLFAKVN-TEDEQQIGGRFQIRSIPTMVLFKA 116
Cdd:pfam13899  14 AERGKPVLVDFGADWCFTCQVLERDFLSheeVKAALAKNFVLLRLDwTSRDANITRAFDGQGVPHIAFLDP 84

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        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 503795763  57 LVDFWAPWCGPCRTMAPQFEQAGR---AMRGRVLFAKVNTEDE--QQIGGRFQIRSIPTMVLFKAGKELA 121
Cdd:cd02992   23 LVEFYASWCGHCRAFAPTWKKLARdlrKWRPVVRVAAVDCADEenVALCRDFGVTGYPTLRYFPPFSKEA 92

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 503795763  57 LVDFWAPWCGPCRTMAPQFEQAGRAMRGRVL-FAKVNTEDEQQIGGRFQI------RSIPTMVLFKAGKELAR 122
Cdd:cd02962   51 LVEFFTTWSPECVNFAPVFAELSLKYNNNNLkFGKIDIGRFPNVAEKFRVstsplsKQLPTIILFQGGKEVAR 123

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 503795763  57 LVDFWAPWCGPCRTMAPQFEQ-AGRAMRGRVLFAKVNTEDEQQIGGRFQIRSIPTMVLFKAG 117
Cdd:cd02994   20 MIEFYAPWCPACQQLQPEWEEfADWSDDLGINVAKVDVTQEPGLSGRFFVTALPTIYHAKDG 81

TlpA-like family, DsbE (also known as CcmG and CycY) subfamily; DsbE is a membrane-anchored, periplasmic TRX-like reductase containing a CXXC motif that specifically donates reducing equivalents to apocytochrome c via CcmH, another cytochrome c maturation (Ccm) factor with a redox active CXXC motif. Assembly of cytochrome c requires the ligation of heme to reduced thiols of the apocytochrome. In bacteria, this assembly occurs in the periplasm. The reductase activity of DsbE in the oxidizing environment of the periplasm is crucial in the maturation of cytochrome c.

                         10        20        30
                 ....*....|....*....|....*....|..
gi 503795763  55 PVLVDFWAPWCGPCRTMAPQFEQAGRAMRGRV 86
Cdd:cd03010   27 PYLLNVWASWCAPCREEHPVLMALARQGRVPI 58

5'-adenylylsulfate reductase

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 503795763  55 PVLVDFWAPWCGPCRTMAPQFEQAGRAMRGR-VLFAKVNTEDEQQIGGR--FQIRSIPTMVLF 114
Cdd:PLN02309 367 PWLVVLYAPWCPFCQAMEASYEELAEKLAGSgVKVAKFRADGDQKEFAKqeLQLGSFPTILLF 429

Intermembrane transporter PqiABC subunit PqiA [Cell wall/membrane/envelope biogenesis];

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|
gi 503795763   2 ILLCPACGATNRVPQERLGENPRCGKCHALIFPEHPVNLS 41
Cdd:COG2995   13 LIACPHCDLLLRRPPLPPGERARCPRCGAVLHRRKPNSLQ 52

SoxW family; SoxW is a bacterial periplasmic TRX, containing a redox active CXXC motif, encoded by a genetic locus (sox operon) involved in thiosulfate oxidation. Sulfur bacteria oxidize sulfur compounds to provide reducing equivalents for carbon dioxide fixation during autotrophic growth and the respiratory electron transport chain. It is unclear what the role of SoxW is, since it has been found to be dispensable in the oxidation of thiosulfate to sulfate. SoxW is specifically kept in the reduced state by SoxV, which is essential in thiosulfate oxidation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 503795763  21 ENPRCGKCHALifpeHPVNLSNSRFPGYIQKNELPVLVDFwapwcgpcRTMAPqfeqagramrgrVLFAKVNTEDEQQIG 100
Cdd:cd02951   22 SQPGCPYCDKL----KRDYLNDPAVQAYIRAHFVVVYINI--------DGDKE------------VTDFDGEALSEKELA 77

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 503795763 101 GRFQIRSIPTMVLF--KAGKELARVSGAMGAAELQ---RWLAGQG 140
Cdd:cd02951   78 RKYRVRFTPTVIFLdpEGGKEIARLPGYLPPDEFLaylEYVQEKA 122

Phosducin (Phd)-like family, Thioredoxin (TRX) domain containing protein 9 (TxnDC9) subfamily; composed of predominantly uncharacterized eukaryotic proteins, containing a TRX-like domain without the redox active CXXC motif. The gene name for the human protein is TxnDC9. The two characterized members are described as Phd-like proteins, PLP1 of Saccharomyces cerevisiae and PhLP3 of Dictyostelium discoideum. Gene disruption experiments show that both PLP1 and PhLP3 are non-essential proteins. Unlike Phd and most Phd-like proteins, members of this group do not contain the Phd N-terminal helical domain which is implicated in binding to the G protein betagamma subunit.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 503795763  56 VLVDFWAPWCGPCRTMAPQFEQAGRAMRGrVLFAKVNTEDEQQIGGRFQIRSIPTMVLFKAGKELARVSG 125
Cdd:cd02989   25 VVCHFYHPEFFRCKIMDKHLEILAKKHLE-TKFIKVNAEKAPFLVEKLNIKVLPTVILFKNGKTVDRIVG 93

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
                 ....*....|....*....|....*....|....*....|....*..
gi 503795763  52 NELPVLVDFWAPWCGPCRTMAPQFEQAGRAMRGRVLFAKVNTEDEQQ 98
Cdd:cd02959   18 SGKPLMLLIHKTWCGACKALKPKFAESKEISELSHNFVMVNLEDDEE 64