PDIb family, ERp44 subfamily, first redox inactive TRX-like domain b; ERp44 is an endoplasmic reticulum (ER)-resident protein, induced during stress, involved in thiol-mediated ER retention. It contains an N-terminal TRX domain with a CXFS motif followed by two redox inactive TRX-like domains, homologous to the b and b' domains of PDI. Through the formation of reversible mixed disulfides, 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. ERp44 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. Similar to PDI, the b domain of ERp44 is likely involved in binding to substrates.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119579327  55 IQEIRDLAEITTLDRSKRNIIGYFEQKDSDNYRVFERVANILHDDCAFLSAFGDVSKPERYSGDNIIYKPPGHSAPDMVY 134
Cdd:cd03070    1 IKEFRNLDELNNVDRSKRNIIGYFESKDSDEYDNFRKVANILRDDCSFLVGFGDVTKPERPPGDNIIYFPPGHNAPDMVY 80

                 ....*..
gi 119579327 135 LGAMTNF 141
Cdd:cd03070   81 LGSLTNF 87

PDIb family, ERp44 subfamily, first redox inactive TRX-like domain b; ERp44 is an endoplasmic reticulum (ER)-resident protein, induced during stress, involved in thiol-mediated ER retention. It contains an N-terminal TRX domain with a CXFS motif followed by two redox inactive TRX-like domains, homologous to the b and b' domains of PDI. Through the formation of reversible mixed disulfides, 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. ERp44 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. Similar to PDI, the b domain of ERp44 is likely involved in binding to substrates.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119579327  55 IQEIRDLAEITTLDRSKRNIIGYFEQKDSDNYRVFERVANILHDDCAFLSAFGDVSKPERYSGDNIIYKPPGHSAPDMVY 134
Cdd:cd03070    1 IKEFRNLDELNNVDRSKRNIIGYFESKDSDEYDNFRKVANILRDDCSFLVGFGDVTKPERPPGDNIIYFPPGHNAPDMVY 80

                 ....*..
gi 119579327 135 LGAMTNF 141
Cdd:cd03070   81 LGSLTNF 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 119579327    8 DIAQRYRISKYPTLKLFRNGMMMKREYRGQRSVKALADYIRQQKSDPIQEIRDLAEITTLDRSKRN-IIGYFEQKDSDNY 86
Cdd:TIGR01130  66 DLAQKYGVSGYPTLKIFRNGEDSVSDYNGPRDADGIVKYMKKQSGPAVKEIETVADLEAFLADDDVvVIGFFKDLDSELN 145

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 119579327   87 RVFERVANILHDDCAFLSAFGDVSKPERY---SGDNIIYKPPGHSAPDMVYLGAMTN 140
Cdd:TIGR01130 146 DTFLSVAEKLRDVYFFFAHSSDVAAFAKLgafPDSVVLFKPKDEDEKFSKVDGEMDT 202

Thioredoxin-like domain;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 119579327   78 FEQKDSDNYRVFERVANILHDDCAFLSAF-GDVSKPERYSGDNII-YKPPGHSAPDmvYLGAMTNF 141
Cdd:pfam13848   1 FEDKDSPLYEIFRKAAKELKGDVRFGITFsKEVADKYNIKEPAILlFRKFDEETVH--YPGDSINF 64

Thioredoxin domain-containing protein; Provisional

                         10        20        30
                 ....*....|....*....|....*....|....*....
gi 119579327   8 DIAQRYRISKYPTLKLFRNGMMMKREyRGQRSVKALADY 46
Cdd:PTZ00443  97 NLAKRFAIKGYPTLLLFDKGKMYQYE-GGDRSTEKLAAF 134

PDIb family, ERp44 subfamily, first redox inactive TRX-like domain b; ERp44 is an endoplasmic reticulum (ER)-resident protein, induced during stress, involved in thiol-mediated ER retention. It contains an N-terminal TRX domain with a CXFS motif followed by two redox inactive TRX-like domains, homologous to the b and b' domains of PDI. Through the formation of reversible mixed disulfides, 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. ERp44 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. Similar to PDI, the b domain of ERp44 is likely involved in binding to substrates.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119579327  55 IQEIRDLAEITTLDRSKRNIIGYFEQKDSDNYRVFERVANILHDDCAFLSAFGDVSKPERYSGDNIIYKPPGHSAPDMVY 134
Cdd:cd03070    1 IKEFRNLDELNNVDRSKRNIIGYFESKDSDEYDNFRKVANILRDDCSFLVGFGDVTKPERPPGDNIIYFPPGHNAPDMVY 80

                 ....*..
gi 119579327 135 LGAMTNF 141
Cdd:cd03070   81 LGSLTNF 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 119579327    8 DIAQRYRISKYPTLKLFRNGMMMKREYRGQRSVKALADYIRQQKSDPIQEIRDLAEITTLDRSKRN-IIGYFEQKDSDNY 86
Cdd:TIGR01130  66 DLAQKYGVSGYPTLKIFRNGEDSVSDYNGPRDADGIVKYMKKQSGPAVKEIETVADLEAFLADDDVvVIGFFKDLDSELN 145

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 119579327   87 RVFERVANILHDDCAFLSAFGDVSKPERY---SGDNIIYKPPGHSAPDMVYLGAMTN 140
Cdd:TIGR01130 146 DTFLSVAEKLRDVYFFFAHSSDVAAFAKLgafPDSVVLFKPKDEDEKFSKVDGEMDT 202

Protein Disulfide Isomerase (PDIb) family, redox inactive TRX-like domain b; 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, calsequestrin and other PDI-related proteins like ERp72, ERp57, ERp44 and PDIR. PDI, ERp57 (or ERp60), ERp72 and PDIR 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 contain multiple copies of a redox active TRX (a) domain containing a CXXC motif, and one or more redox inactive TRX-like (b) domains. The molecular structure of PDI is abb'a'. Also included in this family is the PDI-related protein ERp27, which contains only redox-inactive TRX-like (b and b') domains. The redox inactive b domains are implicated in substrate recognition.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119579327  55 IQEIRDLAEI-TTLDRSKRNIIGYFEQKDSDNYRVFERVANILHDDcaflSAFGDVSKPER------YSGDNIIYKPP-- 125
Cdd:cd02981    1 VKELTSKEELeKFLDKDDVVVVGFFKDEESEEYKTFEKVAESLRDD----YGFGHTSDKEVakklkvKPGSVVLFKPFee 76

                         90
                 ....*....|....*..
gi 119579327 126 GHSAPDMVYL-GAMTNF 141
Cdd:cd02981   77 EPVEYDGEFTeESLVEF 93

Thioredoxin-like domain;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 119579327   78 FEQKDSDNYRVFERVANILHDDCAFLSAF-GDVSKPERYSGDNII-YKPPGHSAPDmvYLGAMTNF 141
Cdd:pfam13848   1 FEDKDSPLYEIFRKAAKELKGDVRFGITFsKEVADKYNIKEPAILlFRKFDEETVH--YPGDSINF 64

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
                 ....*....|....*....|....*....|....*....|
gi 119579327   8 DIAQRYRISKYPTLKLFRNGMMMKREYRGQRSVKALADYI 47
Cdd:cd02998   66 DLAKKYGVSGFPTLKFFPKGSTEPVKYEGGRDLEDLVKFV 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
                 ....*....|....*....|....*....|....*....|....*
gi 119579327   5 APADIAQRYRISKYPTLKLFRNGmmmKR--EYRGQRSVKALADYI 47
Cdd:cd03005   61 QHRELCSEFQVRGYPTLLLFKDG---EKvdKYKGTRDLDSLKEFV 102

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
                 ....*....|....*....|....*....|....*....
gi 119579327   9 IAQRYRISKYPTLKLFRNGMMMkREYRGQRSVKALADYI 47
Cdd:cd02997   67 LKEEYNVKGFPTFKYFENGKFV-EKYEGERTAEDIIEFM 104

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
                  ....*....|....*....|....*....|....*....|..
gi 119579327    7 ADIAQRYRISKYPTLKLFRNGMMMKrEYRGQRSVKALADYIR 48
Cdd:pfam00085  62 PDLASKYGVRGYPTLIFFKNGQPVD-DYVGARPKDALAAFLK 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
                 ....*....|....*....|....*....|....*....|
gi 119579327   8 DIAQRYRISKYPTLKLFRNGMMMKREYrGQRSVKALADYI 47
Cdd:cd02947   54 ELAEEYGVRSIPTFLFFKNGKEVDRVV-GADPKEELEEFL 92