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 2097225230 127 KELTDDTFEHLTQASSgattgDWFVMFGSTDCVECSRLIPKWEAVGAKLKRR--VNVARINKyTTGASTAKRFNVYETPE 204
Cdd:cd02961     1 VELTDDNFDELVKDSK-----DVLVEFYAPWCGHCKALAPEYEKLAKELKGDgkVVVAKVDC-TANNDLCSEYGVRGYPT 74

                          90       100
                  ....*....|....*....|....*...
gi 2097225230 205 FIFFRHG--KMYRYKIPKyDINSFTSFA 230
Cdd:cd02961    75 IKLFPNGskEPVKYEGPR-TLESLVEFI 101

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 2097225230 126 VKELTDDTFEHLTQASSgattgDWFVM-FGSTDCVECSRLIPKWEAVGAKLKRRVNVARINKyTTGASTAKRFNVYETPE 204
Cdd:pfam00085   2 VVVLTDANFDEVVQKSS-----KPVLVdFYAPWCGPCKMLAPEYEELAQEYKGNVVFAKVDV-DENPDLASKYGVRGYPT 75

                  ....*...
gi 2097225230 205 FIFFRHGK 212
Cdd:pfam00085  76 LIFFKNGQ 83

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 2097225230 127 KELTDDTFEHLTQASSgattgDWFVMFGSTDCVECSRLIPKWEAVGAKLKRR--VNVARINKyTTGASTAKRFNVYETPE 204
Cdd:cd02961     1 VELTDDNFDELVKDSK-----DVLVEFYAPWCGHCKALAPEYEKLAKELKGDgkVVVAKVDC-TANNDLCSEYGVRGYPT 74

                          90       100
                  ....*....|....*....|....*...
gi 2097225230 205 FIFFRHG--KMYRYKIPKyDINSFTSFA 230
Cdd:cd02961    75 IKLFPNGskEPVKYEGPR-TLESLVEFI 101

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 2097225230 147 GDWFVMFGSTDCVECSRLIPKWEAVGAKLKRR---VNVARINKyTTGASTAKRFNVYETPEFIFFRHGKMYRYKIP--KY 221
Cdd:cd03000    16 DIWLVDFYAPWCGHCKKLEPVWNEVGAELKSSgspVRVGKLDA-TAYSSIASEFGVRGYPTIKLLKGDLAYNYRGPrtKD 94

                  ....*.
gi 2097225230 222 DINSFT 227
Cdd:cd03000    95 DIVEFA 100

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 2097225230 125 TVKELTDDTFEHltqassGATTGDWFVMFGSTDCVECSRLIPKWEAVGAKLKRRVNVARINKY--TTGASTAKRFNVYET 202
Cdd:cd03005     1 GVLELTEDNFDH------HIAEGNHFVKFFAPWCGHCKRLAPTWEQLAKKFNNENPSVKIAKVdcTQHRELCSEFQVRGY 74

                          90       100       110
                  ....*....|....*....|....*....|.
gi 2097225230 203 PEFIFFRHGKmyryKIPKY----DINSFTSF 229
Cdd:cd03005    75 PTLLLFKDGE----KVDKYkgtrDLDSLKEF 101

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        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2097225230 126 VKELTDDTFEHLTQassgattGDWFVMFGSTDCVECSRLIPKWEAVGAKLKR-RVNVARINkYTTGASTAKRFNVYETPE 204
Cdd:cd02994     3 VVELTDSNWTLVLE-------GEWMIEFYAPWCPACQQLQPEWEEFADWSDDlGINVAKVD-VTQEPGLSGRFFVTALPT 74

                          90       100
                  ....*....|....*....|....*...
gi 2097225230 205 FIFFRHGKMYRYKIPKyDINSFTSFAKE 232
Cdd:cd02994    75 IYHAKDGVFRRYQGPR-DKEDLISFIEE 101

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 2097225230 150 FVMFGSTDCVECSRLIPKWEAVgAKLKRRVNVARINkYTTGASTAKRFNVYETPEFIFFRHGKM 213
Cdd:cd02947    14 VVDFWAPWCGPCKAIAPVLEEL-AEEYPKVKFVKVD-VDENPELAEEYGVRSIPTFLFFKNGKE 75