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 1720380736 164 VELTEETFNTTVMTS-DSIVLFYATWHAVSMAFLQSYIDVAIKLKGRSTILLTRINCADWSDICTKQNVTAFPVVKLYKE 242
Cdd:cd02961     1 VELTDDNFDELVKDSkDVLVEFYAPWCGHCKALAPEYEKLAKELKGDGKVVVAKVDCTANNDLCSEYGVRGYPTIKLFPN 80

                          90       100
                  ....*....|....*....|.
gi 1720380736 243 GES-PVSYAGMLATKDLLKFI 262
Cdd:cd02961    81 GSKePVKYEGPRTLESLVEFI 101

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 1720380736 164 VELTEETFNTTVMTS-DSIVLFYATWHAVSMAFLQSYIDVAIKLKGRSTILLTRINCADWSDICTKQNVTAFPVVKLYKE 242
Cdd:cd02961     1 VELTDDNFDELVKDSkDVLVEFYAPWCGHCKALAPEYEKLAKELKGDGKVVVAKVDCTANNDLCSEYGVRGYPTIKLFPN 80

                          90       100
                  ....*....|....*....|.
gi 1720380736 243 GES-PVSYAGMLATKDLLKFI 262
Cdd:cd02961    81 GSKePVKYEGPRTLESLVEFI 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 1720380736 164 VELTEETFNTTVMTSDSIVL--FYATW--HAVSMAFLqsYIDVAIKLKGRSTILltRINCADWSDICTKQNVTAFPVVKL 239
Cdd:pfam00085   3 VVLTDANFDEVVQKSSKPVLvdFYAPWcgPCKMLAPE--YEELAQEYKGNVVFA--KVDVDENPDLASKYGVRGYPTLIF 78

                          90       100
                  ....*....|....*....|...
gi 1720380736 240 YKEGESPVSYAGMLATKDLLKFI 262
Cdd:pfam00085  79 FKNGQPVDDYVGARPKDALAAFL 101

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 1720380736 169 ETFNTTVM--TSDSIVLFYATW--HAVSMAflQSYIDVAIKLKGR-STILLTRINcADWSDIcTKQNVTAFPVVKLYKEG 243
Cdd:TIGR01130 354 KNFDEIVLdeTKDVLVEFYAPWcgHCKNLA--PIYEELAEKYKDAeSDVVIAKMD-ATANDV-PPFEVEGFPTIKFVPAG 429

                          90       100
                  ....*....|....*....|.
gi 1720380736 244 E--SPVSYAGMLATKDLLKFI 262
Cdd:TIGR01130 430 KksEPVPYDGDRTLEDFSKFI 450

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 1720380736 164 VELTEETFNTTVMTS-DSIVLFYATWHAVSMAFLQSYIDVAIKLKGRSTILLTRINCADWSDICTKQNVTAFPVVKLYKE 242
Cdd:cd02961     1 VELTDDNFDELVKDSkDVLVEFYAPWCGHCKALAPEYEKLAKELKGDGKVVVAKVDCTANNDLCSEYGVRGYPTIKLFPN 80

                          90       100
                  ....*....|....*....|.
gi 1720380736 243 GES-PVSYAGMLATKDLLKFI 262
Cdd:cd02961    81 GSKePVKYEGPRTLESLVEFI 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 1720380736 164 VELTEETFNTTVMTS--DSIVLFYATW--HAVSMAflQSYIDVAIKLKGRSTILLTRINC-ADWSDICTKQNVTAFPVVK 238
Cdd:cd02998     3 VELTDSNFDKVVGDDkkDVLVEFYAPWcgHCKNLA--PEYEKLAAVFANEDDVVIAKVDAdEANKDLAKKYGVSGFPTLK 80

                          90       100
                  ....*....|....*....|....*
gi 1720380736 239 LYKEGES-PVSYAGMLATKDLLKFI 262
Cdd:cd02998    81 FFPKGSTePVKYEGGRDLEDLVKFV 105

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 1720380736 163 SVELTEETFNTTVMTSDSIVLFYATW--HAVSMAflQSYIDVAIKL-KGRSTILLTRINCADWSDICTKQNVTAFPVVKL 239
Cdd:cd03005     2 VLELTEDNFDHHIAEGNHFVKFFAPWcgHCKRLA--PTWEQLAKKFnNENPSVKIAKVDCTQHRELCSEFQVRGYPTLLL 79

                          90
                  ....*....|....*....
gi 1720380736 240 YKEGESPVSYAGmlaTKDL 258
Cdd:cd03005    80 FKDGEKVDKYKG---TRDL 95

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 1720380736 164 VELTEETFNTTVMTSDSIVL--FYATW--HAVSMAFLqsYIDVAIKLKGRSTILltRINCADWSDICTKQNVTAFPVVKL 239
Cdd:pfam00085   3 VVLTDANFDEVVQKSSKPVLvdFYAPWcgPCKMLAPE--YEELAQEYKGNVVFA--KVDVDENPDLASKYGVRGYPTLIF 78

                          90       100
                  ....*....|....*....|...
gi 1720380736 240 YKEGESPVSYAGMLATKDLLKFI 262
Cdd:pfam00085  79 FKNGQPVDDYVGARPKDALAAFL 101

PDIa family, N-terminal EFP1 subfamily; EFP1 is a binding partner protein of thyroid oxidase (ThOX), also called Duox. ThOX proteins are responsible for the generation of hydrogen peroxide, a crucial substrate of thyroperoxidase, which functions to iodinate thyroglobulin and synthesize thyroid hormones. EFP1 was isolated through a yeast two-hybrid method using the EF-hand fragment of dog Duox1 as a bait. It could be one of the partners in the assembly of a multiprotein complex constituting the thyroid hydrogen peroxide generating system. EFP1 contains two TRX domains related to the redox active TRX domains of protein disulfide isomerase (PDI). This subfamily is composed of the N-terminal TRX domain of EFP1, which contains a CXXS sequence in place of the typical CXXC motif, similar to ERp44. The CXXS motif allows the formation of stable mixed disulfides, crucial for the ER-retention function of ERp44.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720380736 180 SIVLFYATWHAVSMAFLQSYIDVAIKLKgrSTILLTRINCADWSDICTKQ-NVTAFPVVKLYKEGESPVSYAGMLATKDL 258
Cdd:cd03006    32 SLVMYYAPWDAQSQAARQEFEQVAQKLS--DQVLFVAINCWWPQGKCRKQkHFFYFPVIHLYYRSRGPIEYKGPMRAPYM 109

                  ....
gi 1720380736 259 LKFI 262
Cdd:cd03006   110 EKFV 113

thioredoxin; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720380736 167 TEETFNTTVmTSDSIVL--FYATWHAVSMAFLQSYIDVAiklKGRSTILLTRINCADWSDICTKQNVTAFPVVKLYKEGE 244
Cdd:PTZ00051    7 SQAEFESTL-SQNELVIvdFYAEWCGPCKRIAPFYEECS---KEYTKMVFVKVDVDELSEVAEKENITSMPTFKVFKNGS 82

                          90
                  ....*....|....*...
gi 1720380736 245 SPVSYAGmlATKDLLKFI 262
Cdd:PTZ00051   83 VVDTLLG--ANDEALKQL 98

PDIa family, endoplasmic reticulum protein 44 (ERp44) subfamily; ERp44 is an ER-resident protein, induced during stress, involved in thiol-mediated ER retention. It contains an N-terminal TRX domain, similar to that of PDIa, with a CXFS motif followed by two redox inactive TRX-like domains, homologous to the b and b' domains of PDI. The CXFS motif in the N-terminal domain allows ERp44 to form stable reversible mixed disulfides with its substrates. Through this activity, ERp44 mediates the ER localization of Ero1alpha, a protein that oxidizes protein disulfide isomerases into their active form. ERp44 also prevents the secretion of unassembled cargo protein with unpaired cysteines. It also modulates the activity of inositol 1,4,5-triphosphate type I receptor (IP3R1), an intracellular channel protein that mediates calcium release from the ER to the cytosol.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720380736 163 SVELTEETFNTTVMTSD-SIVLFYATWHAVSMAFLQSYIDVAIKLK----GRSTILLTRINCADWSDICTKQNVTAFPVV 237
Cdd:cd02996     3 IVSLTSGNIDDILQSAElVLVNFYADWCRFSQMLHPIFEEAAAKIKeefpDAGKVVWGKVDCDKESDIADRYRINKYPTL 82

                          90       100
                  ....*....|....*....|....*.
gi 1720380736 238 KLYKEGESP-VSYAGMLATKDLLKFI 262
Cdd:cd02996    83 KLFRNGMMMkREYRGQRSVEALAEFV 108

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 1720380736 169 ETFNTTVMTSDSIVL-FYATW--HAVSMAflqSYIDVAIKLKGRSTILltRINCADWSDICTKQNVTAFPVVKLYKEGES 245
Cdd:cd02947     1 EEFEELIKSAKPVVVdFWAPWcgPCKAIA---PVLEELAEEYPKVKFV--KVDVDENPELAEEYGVRSIPTFLFFKNGKE 75

                          90
                  ....*....|....*...
gi 1720380736 246 PVSYAGMLATKDLLKFIQ 263
Cdd:cd02947    76 VDRVVGADPKEELEEFLE 93