Flavin adenine dinucleotide (FAD)-dependent sulfhydryl oxidase; This is a flavin adenine dinucleotide (FAD) binding domain found in Quiescin sulfhydryl oxidases (QSOX) (EC:1.8.3.2). QSOX is a multi-domain disulfide catalyst that is localized primarily to the Golgi apparatus and secreted fluids and has attracted attention due to its over-production in tumors. Structural studies indicate that the closure of the Trx1 domain over the FAD-binding site may enhance the active-site chemistry for disulfide formation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 145580631  318 DKSKLYTVDLESGLHYLLRVELAAHKSLAGAELKTLKDFVTVLAKLFPGRPPVKKLLEMLQEWLASLPLDRIPYNAVLDL 397
Cdd:pfam18371   1 DRSKVYMADLESALHYSLRVELAKHSVLEGEELKALKDYVTVLAKYFPGRPSVKNLLQSLDSWLQSQPETKISYSALLDA 80

                          90       100
                  ....*....|....*....|....
gi 145580631  398 VNNKMRISGIFLTNHIKWVGCQGS 421
Cdd:pfam18371  81 LDNKKEAPGAVLPEEVRWVGCQGS 104

QSOX Trx-like domain; This domain is found in Quiescin sulfhydryl oxidase (QSOX), an oxidoreductase present in Homo sapiens capable of both generating and transferring disulfide modules within a single polypeptide. The domain is thioredoxin-like, hence referred to as Trx1 domain. Trx1 domain has a di-cysteine motif (Cys-X-X-Cys) which is related to the redox-active domains of protein disulfide isomerase. The Trx1 domain is responsible for intramolecular disulfide transfer through the di-cysteine motif.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 145580631  185 PPACPRLDPIQPSDVLSLLDNRGSHYVAIVFESNSSYLGREVILDLIPYESIVVTRALDGDKAFLEKLGVSSVPSCYLIY 264
Cdd:pfam18108   1 PPACPPLQPAHSSEIDEFFQTNNVEYLALIFEANDSYVGREVILDLAQHDNVAVRRVLNTEAMLVKKLGVTVFPSCYLLY 80

                          90       100
                  ....*....|....*....|....*...
gi 145580631  265 PNGSHGLINVVKPLRAFFSSYLKSLPDV 292
Cdd:pfam18108  81 RNGSAIRLPVGGETRFFYRLALQRLPGL 108

Flavin adenine dinucleotide (FAD)-dependent sulfhydryl oxidase; This is a flavin adenine dinucleotide (FAD) binding domain found in Quiescin sulfhydryl oxidases (QSOX) (EC:1.8.3.2). QSOX is a multi-domain disulfide catalyst that is localized primarily to the Golgi apparatus and secreted fluids and has attracted attention due to its over-production in tumors. Structural studies indicate that the closure of the Trx1 domain over the FAD-binding site may enhance the active-site chemistry for disulfide formation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 145580631  318 DKSKLYTVDLESGLHYLLRVELAAHKSLAGAELKTLKDFVTVLAKLFPGRPPVKKLLEMLQEWLASLPLDRIPYNAVLDL 397
Cdd:pfam18371   1 DRSKVYMADLESALHYSLRVELAKHSVLEGEELKALKDYVTVLAKYFPGRPSVKNLLQSLDSWLQSQPETKISYSALLDA 80

                          90       100
                  ....*....|....*....|....
gi 145580631  398 VNNKMRISGIFLTNHIKWVGCQGS 421
Cdd:pfam18371  81 LDNKKEAPGAVLPEEVRWVGCQGS 104

QSOX Trx-like domain; This domain is found in Quiescin sulfhydryl oxidase (QSOX), an oxidoreductase present in Homo sapiens capable of both generating and transferring disulfide modules within a single polypeptide. The domain is thioredoxin-like, hence referred to as Trx1 domain. Trx1 domain has a di-cysteine motif (Cys-X-X-Cys) which is related to the redox-active domains of protein disulfide isomerase. The Trx1 domain is responsible for intramolecular disulfide transfer through the di-cysteine motif.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 145580631  185 PPACPRLDPIQPSDVLSLLDNRGSHYVAIVFESNSSYLGREVILDLIPYESIVVTRALDGDKAFLEKLGVSSVPSCYLIY 264
Cdd:pfam18108   1 PPACPPLQPAHSSEIDEFFQTNNVEYLALIFEANDSYVGREVILDLAQHDNVAVRRVLNTEAMLVKKLGVTVFPSCYLLY 80

                          90       100
                  ....*....|....*....|....*...
gi 145580631  265 PNGSHGLINVVKPLRAFFSSYLKSLPDV 292
Cdd:pfam18108  81 RNGSAIRLPVGGETRFFYRLALQRLPGL 108

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 145580631   63 VWVLDSGSVRGATANSSAAWLVQFYSSWCGHCIGYAPTWRALAGDVRDwasAIRVAALDCMEekNQAVCHDYDIHFYPTF 142
Cdd:pfam00085   2 VVVLTDANFDEVVQKSSKPVLVDFYAPWCGPCKMLAPEYEELAQEYKG---NVVFAKVDVDE--NPDLASKYGVRGYPTL 76

                  ....
gi 145580631  143 RYFK 146
Cdd:pfam00085  77 IFFK 80

disulphide isomerase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 145580631  60 EDAVWVLDSGSVRGATANSSAAwLVQFYSSWCGHCIGYAPTWRALAGDVRDWASAIRVAALDCMEEKNQAvcHDYDIHFY 139
Cdd:PTZ00102  31 SEHVTVLTDSTFDKFITENEIV-LVKFYAPWCGHCKRLAPEYKKAAKMLKEKKSEIVLASVDATEEMELA--QEFGVRGY 107

                         90
                 ....*....|....*.
gi 145580631 140 PTFRYFKAFTKEFTTG 155
Cdd:PTZ00102 108 PTIKFFNKGNPVNYSG 123

Mitochondrial sulfhydryl oxidase involved in the biogenesis of cytosolic Fe/S proteins [Posttranslational modification, protein turnover, chaperones];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 145580631 431 SLWKLFHTLtveASTHPDALVGTGFEDdpqavlqtMRRYVHTF---FGCKECGEHFEEMAKESMDSVKTPDQAILWLWKK 507
Cdd:COG5054   85 SSWTLLHTV---AANYPARPTPQQRDD--------LRSFLFLFsitYPCGECSKHFQKLLDVYPPQVSSREAATTWACEV 153

                 ....*...
gi 145580631 508 HNMVNGRL 515
Cdd:COG5054  154 HNKVNEKL 161

Flavin adenine dinucleotide (FAD)-dependent sulfhydryl oxidase; This is a flavin adenine dinucleotide (FAD) binding domain found in Quiescin sulfhydryl oxidases (QSOX) (EC:1.8.3.2). QSOX is a multi-domain disulfide catalyst that is localized primarily to the Golgi apparatus and secreted fluids and has attracted attention due to its over-production in tumors. Structural studies indicate that the closure of the Trx1 domain over the FAD-binding site may enhance the active-site chemistry for disulfide formation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 145580631  318 DKSKLYTVDLESGLHYLLRVELAAHKSLAGAELKTLKDFVTVLAKLFPGRPPVKKLLEMLQEWLASLPLDRIPYNAVLDL 397
Cdd:pfam18371   1 DRSKVYMADLESALHYSLRVELAKHSVLEGEELKALKDYVTVLAKYFPGRPSVKNLLQSLDSWLQSQPETKISYSALLDA 80

                          90       100
                  ....*....|....*....|....
gi 145580631  398 VNNKMRISGIFLTNHIKWVGCQGS 421
Cdd:pfam18371  81 LDNKKEAPGAVLPEEVRWVGCQGS 104

QSOX Trx-like domain; This domain is found in Quiescin sulfhydryl oxidase (QSOX), an oxidoreductase present in Homo sapiens capable of both generating and transferring disulfide modules within a single polypeptide. The domain is thioredoxin-like, hence referred to as Trx1 domain. Trx1 domain has a di-cysteine motif (Cys-X-X-Cys) which is related to the redox-active domains of protein disulfide isomerase. The Trx1 domain is responsible for intramolecular disulfide transfer through the di-cysteine motif.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 145580631  185 PPACPRLDPIQPSDVLSLLDNRGSHYVAIVFESNSSYLGREVILDLIPYESIVVTRALDGDKAFLEKLGVSSVPSCYLIY 264
Cdd:pfam18108   1 PPACPPLQPAHSSEIDEFFQTNNVEYLALIFEANDSYVGREVILDLAQHDNVAVRRVLNTEAMLVKKLGVTVFPSCYLLY 80

                          90       100
                  ....*....|....*....|....*...
gi 145580631  265 PNGSHGLINVVKPLRAFFSSYLKSLPDV 292
Cdd:pfam18108  81 RNGSAIRLPVGGETRFFYRLALQRLPGL 108

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 145580631  77 NSSAAWLVQFYSSWCGHCIGYAPTWRALAGDVRdWASAIRVAALDCmeEKNQAVCHDYDIHFYPTFRYFKAFTKEFttgE 156
Cdd:cd02961   13 KDSKDVLVEFYAPWCGHCKALAPEYEKLAKELK-GDGKVVVAKVDC--TANNDLCSEYGVRGYPTIKLFPNGSKEP---V 86

                         90       100
                 ....*....|....*....|
gi 145580631 157 NFKGPdrelRTVrQTMIDFL 176
Cdd:cd02961   87 KYEGP----RTL-ESLVEFI 101

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 145580631  62 AVWVLDSGSVRGATANSSAAWLVQFYSSWCGHCIGYAPTWRALAgdvRDWASAIRVAALDCmeEKNQAVCHDYDIHFYPT 141
Cdd:cd03004    2 SVITLTPEDFPELVLNRKEPWLVDFYAPWCGPCQALLPELRKAA---RALKGKVKVGSVDC--QKYESLCQQANIRAYPT 76

                         90
                 ....*....|.
gi 145580631 142 FRYFKAFTKEF 152
Cdd:cd03004   77 IRLYPGNASKY 87

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 145580631  78 SSAAWLVQFYSSWCGHCIGYAPTWRALAGDVRDWASAIRVAALDCMEEKNqaVCHDYDIHFYPTFRYFKAFTKefttGEN 157
Cdd:cd03005   15 AEGNHFVKFFAPWCGHCKRLAPTWEQLAKKFNNENPSVKIAKVDCTQHRE--LCSEFQVRGYPTLLLFKDGEK----VDK 88

                         90
                 ....*....|....*....
gi 145580631 158 FKGPdRELrtvrQTMIDFL 176
Cdd:cd03005   89 YKGT-RDL----DSLKEFV 102

PDIa family, N-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 comprised of the first TRX domain of ERdj5 located after the DnaJ domain at the N-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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 145580631  66 LDSGSVRGATaNSSAAWLVQFYSSWCGHCIGYAPTWRALAGDVRdwaSAIRVAALDCMEekNQAVCHDYDIHFYPTFRYF 145
Cdd:cd03003    6 LDRGDFDAAV-NSGEIWFVNFYSPRCSHCHDLAPTWREFAKEMD---GVIRIGAVNCGD--DRMLCRSQGVNSYPSLYVF 79

                         90
                 ....*....|....*..
gi 145580631 146 KA-FTKEFTTGENFKGP 161
Cdd:cd03003   80 PSgMNPEKYYGDRSKES 96

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 145580631   63 VWVLDSGSVRGATANSSAAWLVQFYSSWCGHCIGYAPTWRALAGDVRDwasAIRVAALDCMEekNQAVCHDYDIHFYPTF 142
Cdd:pfam00085   2 VVVLTDANFDEVVQKSSKPVLVDFYAPWCGPCKMLAPEYEELAQEYKG---NVVFAKVDVDE--NPDLASKYGVRGYPTL 76

                  ....
gi 145580631  143 RYFK 146
Cdd:pfam00085  77 IFFK 80

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 145580631   83 LVQFYSSWCGHCIGYAPTWRALAGDVRDWASAIRVAALDCMEEKnqAVCHDYDIHFYPTFRYFK 146
Cdd:TIGR01130  22 LVEFYAPWCGHCKSLAPEYEKAADELKKKGPPIKLAKVDATEEK--DLAQKYGVSGYPTLKIFR 83

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 145580631   83 LVQFYSSWCGHCIGYAPTWRALAGDVRDWASAIRVAALDCMEekNQAvcHDYDIHFYPTFRYFKAFTKefTTGENFKGpD 162
Cdd:TIGR01130 368 LVEFYAPWCGHCKNLAPIYEELAEKYKDAESDVVIAKMDATA--NDV--PPFEVEGFPTIKFVPAGKK--SEPVPYDG-D 440

                          90       100
                  ....*....|....*....|....*.
gi 145580631  163 RELrtvrQTMIDFLQNH-TEGSRPPA 187
Cdd:TIGR01130 441 RTL----EDFSKFIAKHaTFPLEGKA 462

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 145580631  83 LVQFYSSWCGHCIGYAPTWRALAGDVRDwASAIRVAALDCmeEKNQaVCHDYDIHFYPTFRYFKAFTKE 151
Cdd:cd02995   22 LVEFYAPWCGHCKALAPIYEELAEKLKG-DDNVVIAKMDA--TAND-VPSEFVVDGFPTILFFPAGDKS 86

Chaperedoxin CnoX, contains thioredoxin-like and TPR-like domains, YbbN/TrxSC family [Posttranslational modification, protein turnover, chaperones];

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 145580631  83 LVQFYSSWCGHCIGYAPTWRALAgdvRDWASAIRVAALDCmeEKNQAVCHDYDIHFYPTFRYFK 146
Cdd:COG3118   22 LVDFWAPWCGPCKMLAPVLEELA---AEYGGKVKFVKVDV--DENPELAAQFGVRSIPTLLLFK 80

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
                 ....*....|....*....|....*....|....*....|....*.
gi 145580631  82 WLVQFYSSWCGHCIGYAPTWRALAgdvrDWASA--IRVAALDCMEE 125
Cdd:cd02994   19 WMIEFYAPWCPACQQLQPEWEEFA----DWSDDlgINVAKVDVTQE 60

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

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*...
gi 145580631  82 WLVQFYSSWCGHCIGYAPTWRALAGDVRDwasaIRVAALDCMEEKNQA 129
Cdd:COG0526   31 VLVNFWATWCPPCRAEMPVLKELAEEYGG----VVFVGVDVDENPEAV 74