PDIa family, endoplasmic reticulum protein 44 (ERp44)-like subfamily; composed of uncharacterized PDI-like eukaryotic proteins containing only one redox active TRX (a) domain with a CXXS motif, similar to ERp44. CXXS is still a redox active motif; however, the mixed disulfide formed with the substrate is more stable than those formed by CXXC motif proteins. PDI-related proteins are usually involved in the oxidative protein folding in the ER by acting as catalysts and folding assistants. ERp44 is involved in thiol-mediated retention in the ER.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1184495164 120 FTLKILNMSQDLMDFLNPNGsdcTLVLFYTPWCRFSASLAPHFNSLPRAFPALHFLALDAS-QHSSLSTRFGTVAVPNIL 198
Cdd:cd02999     1 PPEEVLNIALDLMAFNREDY---TAVLFYASWCPFSASFRPHFNALSSMFPQIRHLAIEESsIKPSLLSRYGVVGFPTIL 77

                          90       100
                  ....*....|....*....|....*
gi 1184495164 199 LFQGAkPMARFNHTdRTLETLKIFI 223
Cdd:cd02999    78 LFNST-PRVRYNGT-RTLDSLAAFY 100

PDIa family, endoplasmic reticulum protein 44 (ERp44)-like subfamily; composed of uncharacterized PDI-like eukaryotic proteins containing only one redox active TRX (a) domain with a CXXS motif, similar to ERp44. CXXS is still a redox active motif; however, the mixed disulfide formed with the substrate is more stable than those formed by CXXC motif proteins. PDI-related proteins are usually involved in the oxidative protein folding in the ER by acting as catalysts and folding assistants. ERp44 is involved in thiol-mediated retention in the ER.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1184495164 120 FTLKILNMSQDLMDFLNPNGsdcTLVLFYTPWCRFSASLAPHFNSLPRAFPALHFLALDAS-QHSSLSTRFGTVAVPNIL 198
Cdd:cd02999     1 PPEEVLNIALDLMAFNREDY---TAVLFYASWCPFSASFRPHFNALSSMFPQIRHLAIEESsIKPSLLSRYGVVGFPTIL 77

                          90       100
                  ....*....|....*....|....*
gi 1184495164 199 LFQGAkPMARFNHTdRTLETLKIFI 223
Cdd:cd02999    78 LFNST-PRVRYNGT-RTLDSLAAFY 100

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1184495164 144 LVLFYTPWCRFSASLAPHFNSLPRAF-PALHFLALDASQHSSLSTRFGTVAVPNILLFQGAKPMARF 209
Cdd:COG3118    22 LVDFWAPWCGPCKMLAPVLEELAAEYgGKVKFVKVDVDENPELAAQFGVRSIPTLLLFKDGQPVDRF 88

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 1184495164 133 DFLNPNgsDCTLVLFYTPWCRFSASLAPHFNS----LPRAFPALHFLALDASQHSSLSTRFGTVAVPNILLFQGAKPmAR 208
Cdd:TIGR01130  13 DFIKSH--EFVLVEFYAPWCGHCKSLAPEYEKaadeLKKKGPPIKLAKVDATEEKDLAQKYGVSGYPTLKIFRNGED-SV 89

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1184495164 209 FNHTD-RTLETLKIFIFNQTG-----IEAKKNV 235
Cdd:TIGR01130  90 SDYNGpRDADGIVKYMKKQSGpavkeIETVADL 122

PDIa family, endoplasmic reticulum protein 44 (ERp44)-like subfamily; composed of uncharacterized PDI-like eukaryotic proteins containing only one redox active TRX (a) domain with a CXXS motif, similar to ERp44. CXXS is still a redox active motif; however, the mixed disulfide formed with the substrate is more stable than those formed by CXXC motif proteins. PDI-related proteins are usually involved in the oxidative protein folding in the ER by acting as catalysts and folding assistants. ERp44 is involved in thiol-mediated retention in the ER.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1184495164 120 FTLKILNMSQDLMDFLNPNGsdcTLVLFYTPWCRFSASLAPHFNSLPRAFPALHFLALDAS-QHSSLSTRFGTVAVPNIL 198
Cdd:cd02999     1 PPEEVLNIALDLMAFNREDY---TAVLFYASWCPFSASFRPHFNALSSMFPQIRHLAIEESsIKPSLLSRYGVVGFPTIL 77

                          90       100
                  ....*....|....*....|....*
gi 1184495164 199 LFQGAkPMARFNHTdRTLETLKIFI 223
Cdd:cd02999    78 LFNST-PRVRYNGT-RTLDSLAAFY 100

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1184495164 138 NGSDCTLVLFYTPWCRFSASLAPHFNSLPRAFPALHFLALDASQHSSLSTRFGTVAVPNILLFQGAKPMARF 209
Cdd:cd02947     8 KSAKPVVVDFWAPWCGPCKAIAPVLEELAEEYPKVKFVKVDVDENPELAEEYGVRSIPTFLFFKNGKEVDRV 79

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 1184495164 143 TLVLFYTPWCRFSASLAPHFNSLPRAF---PALHFLALDASQ-HSSLSTRFGTVAVPNILLFQ--GAKPMArFNhTDRTL 216
Cdd:cd02998    21 VLVEFYAPWCGHCKNLAPEYEKLAAVFaneDDVVIAKVDADEaNKDLAKKYGVSGFPTLKFFPkgSTEPVK-YE-GGRDL 98

                  ....*..
gi 1184495164 217 ETLKIFI 223
Cdd:cd02998    99 EDLVKFV 105

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 1184495164 138 NGSDCTLVLFYTPWCRFSASLAPHF----NSLPRAFPALH---FLALDASQHSSLSTRFGTVAVPNILLFQGAKPMARFN 210
Cdd:cd02996    16 QSAELVLVNFYADWCRFSQMLHPIFeeaaAKIKEEFPDAGkvvWGKVDCDKESDIADRYRINKYPTLKLFRNGMMMKREY 95

                          90
                  ....*....|...
gi 1184495164 211 HTDRTLETLKIFI 223
Cdd:cd02996    96 RGQRSVEALAEFV 108

TRX domain, PICOT (for PKC-interacting cousin of TRX) subfamily; PICOT is a protein that interacts with protein kinase C (PKC) theta, a calcium independent PKC isoform selectively expressed in skeletal muscle and T lymphocytes. PICOT contains an N-terminal TRX-like domain, which does not contain the catalytic CXXC motif, followed by one to three glutaredoxin domains. The TRX-like domain is required for interaction with PKC theta. PICOT inhibits the activation of c-Jun N-terminal kinase and the transcription factors, AP-1 and NF-kB, induced by PKC theta or T-cell activating stimuli.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1184495164 129 QDLMDFLNPNGSDCTLVLFYTPWCRFSASLAPHFNSLPR-AFPALHFLALDASQHSSLSTRFGTVAVPNILLFQGAKPMA 207
Cdd:cd02984     3 EEFEELLKSDASKLLVLHFWAPWAEPCKQMNQVFEELAKeAFPSVLFLSIEAEELPEISEKFEITAVPTFVFFRNGTIVD 82

                  .
gi 1184495164 208 R 208
Cdd:cd02984    83 R 83

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 1184495164 143 TLVLFYTPWCRFSASLAPHFNSLPRAF----PALHFLALDASQHSSLSTRFGTVAVPNILLFQGAKPMARFNHTdRTLET 218
Cdd:cd03005    19 HFVKFFAPWCGHCKRLAPTWEQLAKKFnnenPSVKIAKVDCTQHRELCSEFQVRGYPTLLLFKDGEKVDKYKGT-RDLDS 97

                  ....*
gi 1184495164 219 LKIFI 223
Cdd:cd03005    98 LKEFV 102

Thioredoxin (TRX) superfamily; a large, diverse group of proteins containing a TRX-fold. Many members contain a classic TRX domain with a redox active CXXC motif. They function as protein disulfide oxidoreductases (PDOs), altering the redox state of target proteins via the reversible oxidation of their active site dithiol. The PDO members of this superfamily include TRX, protein disulfide isomerase (PDI), tlpA-like, glutaredoxin, NrdH redoxin, and the bacterial Dsb (DsbA, DsbC, DsbG, DsbE, DsbDgamma) protein families. Members of the superfamily that do not function as PDOs but contain a TRX-fold domain include phosducins, peroxiredoxins and glutathione (GSH) peroxidases, SCO proteins, GSH transferases (GST, N-terminal domain), arsenic reductases, TRX-like ferredoxins and calsequestrin, among others.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1184495164 144 LVLFYTPWCRFSASLAPHFNSLPRAFPALHFLALDASQHSSL---STRFGTVAVPNILLFQG 202
Cdd:cd01659     1 LVLFYAPWCPFCQALRPVLAELALLNKGVKFEAVDVDEDPALekeLKRYGVGGVPTLVVFGP 62

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        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1184495164 144 LVLFYTPWCRFSASLAPHFNSLPRAF---PALHFLALDASQ---HSSLSTRfgtvAVPNILLFQ--GAKPMARFNhTDRT 215
Cdd:cd02995    22 LVEFYAPWCGHCKALAPIYEELAEKLkgdDNVVIAKMDATAndvPSEFVVD----GFPTILFFPagDKSNPIKYE-GDRT 96

                  ....*...
gi 1184495164 216 LETLKIFI 223
Cdd:cd02995    97 LEDLIKFI 104

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 1184495164 133 DFLNPNgsDCTLVLFYTPWCRFSASLAPHFNS----LPRAFPALHFLALDASQHSSLSTRFGTVAVPNILLFQGAKPmAR 208
Cdd:TIGR01130  13 DFIKSH--EFVLVEFYAPWCGHCKSLAPEYEKaadeLKKKGPPIKLAKVDATEEKDLAQKYGVSGYPTLKIFRNGED-SV 89

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1184495164 209 FNHTD-RTLETLKIFIFNQTG-----IEAKKNV 235
Cdd:TIGR01130  90 SDYNGpRDADGIVKYMKKQSGpavkeIETVADL 122

PDI family, MPD1-like subfamily; composed of eukaryotic proteins similar to Saccharomyces cerevisiae MPD1 protein, which contains a single redox active TRX domain located at the N-terminus, and an ER retention signal at the C-terminus indicative of an ER-resident protein. MPD1 has been shown to suppress the maturation defect of carboxypeptidase Y caused by deletion of the yeast PDI1 gene. Other characterized members of this subfamily include the Aspergillus niger prpA protein and Giardia PDI-1. PrpA is non-essential to strain viability, however, its transcript level is induced by heterologous protein expression suggesting a possible role in oxidative protein folding during high protein production. Giardia PDI-1 has the ability to refold scrambled RNase and exhibits transglutaminase activity.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1184495164 143 TLVLFYTPWCRFSASLAPHFNSLPRAF-PALHFLAL--DASQHSSLSTRFGTVAVPNILLFQGAKPMAR 208
Cdd:cd03002    21 TLVEFYAPWCGHCKNLKPEYAKAAKELdGLVQVAAVdcDEDKNKPLCGKYGVQGFPTLKVFRPPKKASK 89

thioredoxin; Provisional

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1184495164 139 GSDCTLVLFYTPWCRFSASLAPHFNSLPRAFPALHFLALDASQHSSLSTRFGTVAVPNILLFQGAKPMARF 209
Cdd:PTZ00051   17 QNELVIVDFYAEWCGPCKRIAPFYEECSKEYTKMVFVKVDVDELSEVAEKENITSMPTFKVFKNGSVVDTL 87

thioredoxin TrxA;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1184495164 123 KILNMSQDLMDFLNPNGSDCTLVLFYTPWCRFSASLAPHFNSLPRAFPA-LHFLALDASQHSSLSTRFGTVAVPNILLFQ 201
Cdd:PRK09381    4 KIIHLTDDSFDTDVLKADGAILVDFWAEWCGPCKMIAPILDEIADEYQGkLTVAKLNIDQNPGTAPKYGIRGIPTLLLFK 83

                  ....*.
gi 1184495164 202 GAKPMA 207
Cdd:PRK09381   84 NGEVAA 89

thioredoxin 2; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1184495164 120 FTLKILNMSQDLMD-FLNpngSDCTLVL-FYTPWCRFSASLAPHFNSLPRAFPA-LHFLALDASQHSSLSTRFGTVAVPN 196
Cdd:PRK10996   33 FDGEVINATGETLDkLLQ---DDLPVVIdFWAPWCGPCRNFAPIFEDVAAERSGkVRFVKVNTEAERELSARFRIRSIPT 109

                          90       100
                  ....*....|....*....|...
gi 1184495164 197 ILLFQ---------GAKPMARFN 210
Cdd:PRK10996  110 IMIFKngqvvdmlnGAVPKAPFD 132