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 115311850  312 DRAKLYTADLESGLHYLLRVELAAHRSLAGAQLKTFRDFVTVVAKLFPGRPAVKKLLETLQEWLANLPLDKIPYNAILDL 391
Cdd:pfam18371   1 DRSKVYMADLESALHYSLRVELAKHSVLEGEELKALKDYVTVLAKYFPGRPSVKNLLQSLDSWLQSQPETKISYSALLDA 80

                          90       100
                  ....*....|....*....|....
gi 115311850  392 VNNKMQISGIFLTSHVKWVGCQGS 415
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 115311850  179 PPACPPLDPIQSSDILSFMDSHSGQYHAIVFESNGSYVGREVILDLIPYENIMVSRALDTDKAFLGTLGITSVPSCYLIY 258
Cdd:pfam18108   1 PPACPPLQPAHSSEIDEFFQTNNVEYLALIFEANDSYVGREVILDLAQHDNVAVRRVLNTEAMLVKKLGVTVFPSCYLLY 80

                          90       100
                  ....*....|....*....|....*...
gi 115311850  259 PNGSHGLVNVAKPLRSFFSSHLKSLPDV 286
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 115311850  312 DRAKLYTADLESGLHYLLRVELAAHRSLAGAQLKTFRDFVTVVAKLFPGRPAVKKLLETLQEWLANLPLDKIPYNAILDL 391
Cdd:pfam18371   1 DRSKVYMADLESALHYSLRVELAKHSVLEGEELKALKDYVTVLAKYFPGRPSVKNLLQSLDSWLQSQPETKISYSALLDA 80

                          90       100
                  ....*....|....*....|....
gi 115311850  392 VNNKMQISGIFLTSHVKWVGCQGS 415
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 115311850  179 PPACPPLDPIQSSDILSFMDSHSGQYHAIVFESNGSYVGREVILDLIPYENIMVSRALDTDKAFLGTLGITSVPSCYLIY 258
Cdd:pfam18108   1 PPACPPLQPAHSSEIDEFFQTNNVEYLALIFEANDSYVGREVILDLAQHDNVAVRRVLNTEAMLVKKLGVTVFPSCYLLY 80

                          90       100
                  ....*....|....*....|....*...
gi 115311850  259 PNGSHGLVNVAKPLRSFFSSHLKSLPDV 286
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 115311850   57 VWLLDSGSVRSATGNSSAAWLVQFHSSWCGHCIGYAPTWRALAADVRDwaaAIRVAALDCAEekNQDVCRTYDIHFYPTF 136
Cdd:pfam00085   2 VVVLTDANFDEVVQKSSKPVLVDFYAPWCGPCKMLAPEYEELAQEYKG---NVVFAKVDVDE--NPDLASKYGVRGYPTL 76

                  ....
gi 115311850  137 RYFK 140
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 115311850   77 LVQFHSSWCGHCIGYAPTWRALAADVRDWAAAIRVAALDCAEEKnqDVCRTYDIHFYPTFRYFK 140
Cdd:TIGR01130  22 LVEFYAPWCGHCKSLAPEYEKAADELKKKGPPIKLAKVDATEEK--DLAQKYGVSGYPTLKIFR 83

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 115311850  312 DRAKLYTADLESGLHYLLRVELAAHRSLAGAQLKTFRDFVTVVAKLFPGRPAVKKLLETLQEWLANLPLDKIPYNAILDL 391
Cdd:pfam18371   1 DRSKVYMADLESALHYSLRVELAKHSVLEGEELKALKDYVTVLAKYFPGRPSVKNLLQSLDSWLQSQPETKISYSALLDA 80

                          90       100
                  ....*....|....*....|....
gi 115311850  392 VNNKMQISGIFLTSHVKWVGCQGS 415
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 115311850  179 PPACPPLDPIQSSDILSFMDSHSGQYHAIVFESNGSYVGREVILDLIPYENIMVSRALDTDKAFLGTLGITSVPSCYLIY 258
Cdd:pfam18108   1 PPACPPLQPAHSSEIDEFFQTNNVEYLALIFEANDSYVGREVILDLAQHDNVAVRRVLNTEAMLVKKLGVTVFPSCYLLY 80

                          90       100
                  ....*....|....*....|....*...
gi 115311850  259 PNGSHGLVNVAKPLRSFFSSHLKSLPDV 286
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 115311850  71 NSSAAWLVQFHSSWCGHCIGYAPTWRALAADVRdWAAAIRVAALDCAEekNQDVCRTYDIHFYPTFRYFKAFTKEFttgE 150
Cdd:cd02961   13 KDSKDVLVEFYAPWCGHCKALAPEYEKLAKELK-GDGKVVVAKVDCTA--NNDLCSEYGVRGYPTIKLFPNGSKEP---V 86

                         90       100
                 ....*....|....*....|
gi 115311850 151 NFKGPdrelRTVrQTMIDFL 170
Cdd:cd02961   87 KYEGP----RTL-ESLVEFI 101

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 115311850  60 LDSGSVRSATGNSSAAWLVQFHSSWCGHCIGYAPTWRALAADVRDwAAAIRVAALDCaEEKNQDVCRTYDIHFYPTFRYF 139
Cdd:cd02998    5 LTDSNFDKVVGDDKKDVLVEFYAPWCGHCKNLAPEYEKLAAVFAN-EDDVVIAKVDA-DEANKDLAKKYGVSGFPTLKFF 82

                         90       100
                 ....*....|....*....|
gi 115311850 140 KAFTKEfttGENFKGpDREL 159
Cdd:cd02998   83 PKGSTE---PVKYEG-GRDL 98

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 115311850  60 LDSGSVRSATgNSSAAWLVQFHSSWCGHCIGYAPTWRALAADVRdwaAAIRVAALDCAEekNQDVCRTYDIHFYPTFRYF 139
Cdd:cd03003    6 LDRGDFDAAV-NSGEIWFVNFYSPRCSHCHDLAPTWREFAKEMD---GVIRIGAVNCGD--DRMLCRSQGVNSYPSLYVF 79

                         90
                 ....*....|....*..
gi 115311850 140 KA-FTKEFTTGENFKGP 155
Cdd:cd03003   80 PSgMNPEKYYGDRSKES 96

PDIa family, P5 subfamily; composed of eukaryotic proteins similar to human P5, a PDI-related protein with a domain structure of aa'b (where a and a' are redox active TRX domains and b is a redox inactive TRX-like domain). Like PDI, P5 is located in the endoplasmic reticulum (ER) and displays both isomerase and chaperone activities, which are independent of each other. Compared to PDI, the isomerase and chaperone activities of P5 are lower. The first cysteine in the CXXC motif of both redox active domains in P5 is necessary for isomerase activity. The P5 gene was first isolated as an amplified gene from a hydroxyurea-resistant hamster cell line. The zebrafish P5 homolog has been implicated to play a critical role in establishing left/right asymmetries in the embryonic midline. Some members of this subfamily are P5-like proteins containing only one redox active TRX domain.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 115311850  71 NSSAAWLVQFHSSWCGHCIGYAPTWRALAADVRDwaaAIRVAALDCaeEKNQDVCRTYDIHFYPTFRYFKA 141
Cdd:cd03001   16 NSDDVWLVEFYAPWCGHCKNLAPEWKKAAKALKG---IVKVGAVDA--DVHQSLAQQYGVRGFPTIKVFGA 81

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 115311850  76 WLVQFHSSWCGHCIGYAPTWRALAADVRDWAAAIRVAALDCAeeKNQDVCRTYDIHFYPTFRYFK---AFtkefttgeNF 152
Cdd:cd03000   18 WLVDFYAPWCGHCKKLEPVWNEVGAELKSSGSPVRVGKLDAT--AYSSIASEFGVRGYPTIKLLKgdlAY--------NY 87

                         90
                 ....*....|....*..
gi 115311850 153 KGPdrelRTvRQTMIDF 169
Cdd:cd03000   88 RGP----RT-KDDIVEF 99

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 115311850   77 LVQFHSSWCGHCIGYAPTWRALAADVRDWAAAIRVAALDCAEEKnqDVCRTYDIHFYPTFRYFK 140
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 115311850   77 LVQFHSSWCGHCIGYAPTWRALAADVRDWAAAIRVAALDCAEeknQDVcRTYDIHFYPTFRYFKAFTKefTTGENFKGpD 156
Cdd:TIGR01130 368 LVEFYAPWCGHCKNLAPIYEELAEKYKDAESDVVIAKMDATA---NDV-PPFEVEGFPTIKFVPAGKK--SEPVPYDG-D 440

                          90
                  ....*....|....*..
gi 115311850  157 RELrtvrQTMIDFLQNH 173
Cdd:TIGR01130 441 RTL----EDFSKFIAKH 453

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 115311850  77 LVQFHSSWCGHCIGYAPTWRALAADVRDwaaaIRVAALDCaeEKNQDVCRTYDIHFYPTFRYFK 140
Cdd:cd02947   14 VVDFWAPWCGPCKAIAPVLEELAEEYPK----VKFVKVDV--DENPELAEEYGVRSIPTFLFFK 71

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

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 115311850  77 LVQFHSSWCGHCIGYAPTWRALAADVRDwaaAIRVAALDCaeEKNQDVCRTYDIHFYPTFRYFK 140
Cdd:COG3118   22 LVDFWAPWCGPCKMLAPVLEELAAEYGG---KVKFVKVDV--DENPELAAQFGVRSIPTLLLFK 80

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

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 115311850  76 WLVQFHSSWCGHCIGYAPTWRALAA----------DVRDWAAAIRVAALDC------AEEKNQDVCRTYDIHFYPTF 136
Cdd:COG0526   31 VLVNFWATWCPPCRAEMPVLKELAEeyggvvfvgvDVDENPEAVKAFLKELglpypvLLDPDGELAKAYGVRGIPTT 107