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 68163437 171 FTLKILNMSQDLMDFLNPNGsdcTLVLFYTPWCRFSASLAPHFNSLPRAFPTLGFLALDAS-QHSSLSTRFGTVAVPNIL 249
Cdd:cd02999   1 PPEEVLNIALDLMAFNREDY---TAVLFYASWCPFSASFRPHFNALSSMFPQIRHLAIEESsIKPSLLSRYGVVGFPTIL 77

                        90       100
                ....*....|....*....|....*
gi 68163437 250 LFQGAkPMARFNHTdRTLETLKIFI 274
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 68163437 171 FTLKILNMSQDLMDFLNPNGsdcTLVLFYTPWCRFSASLAPHFNSLPRAFPTLGFLALDAS-QHSSLSTRFGTVAVPNIL 249
Cdd:cd02999   1 PPEEVLNIALDLMAFNREDY---TAVLFYASWCPFSASFRPHFNALSSMFPQIRHLAIEESsIKPSLLSRYGVVGFPTIL 77

                        90       100
                ....*....|....*....|....*
gi 68163437 250 LFQGAkPMARFNHTdRTLETLKIFI 274
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 68163437 195 LVLFYTPWCRFSASLAPHFNSLPRAF-PTLGFLALDASQHSSLSTRFGTVAVPNILLFQGAKPMARF 260
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 68163437   194 TLVLFYTPWCRFSASLAPHFNSLPRAF----PTLGFLALDASQ--HSSLSTRfgtvAVPNILLF-QGAK-PMARFNhTDR 265
Cdd:TIGR01130 367 VLVEFYAPWCGHCKNLAPIYEELAEKYkdaeSDVVIAKMDATAndVPPFEVE----GFPTIKFVpAGKKsEPVPYD-GDR 441

                          90
                  ....*....|....*...
gi 68163437   266 TLETLKIFIFNQTGIEAK 283
Cdd:TIGR01130 442 TLEDFSKFIAKHATFPLE 459

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 68163437 171 FTLKILNMSQDLMDFLNPNGsdcTLVLFYTPWCRFSASLAPHFNSLPRAFPTLGFLALDAS-QHSSLSTRFGTVAVPNIL 249
Cdd:cd02999   1 PPEEVLNIALDLMAFNREDY---TAVLFYASWCPFSASFRPHFNALSSMFPQIRHLAIEESsIKPSLLSRYGVVGFPTIL 77

                        90       100
                ....*....|....*....|....*
gi 68163437 250 LFQGAkPMARFNHTdRTLETLKIFI 274
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 68163437 189 NGSDCTLVLFYTPWCRFSASLAPHFNSLPRAFPTLGFLALDASQHSSLSTRFGTVAVPNILLFQGAKPMARF 260
Cdd:cd02947   8 KSAKPVVVDFWAPWCGPCKAIAPVLEELAEEYPKVKFVKVDVDENPELAEEYGVRSIPTFLFFKNGKEVDRV 79

Thioredoxin domain-containing protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 68163437  195 LVLFYTPWCRFSASLAPHFNSLPRAFPTLGFLA-LDASQHSSLSTRFGTVAVPNILLFQGAKpMARFNHTDRTLETLKIF 273
Cdd:PTZ00443  56 FVKFYAPWCSHCRKMAPAWERLAKALKGQVNVAdLDATRALNLAKRFAIKGYPTLLLFDKGK-MYQYEGGDRSTEKLAAF 134

                 ...
gi 68163437  274 IFN 276
Cdd:PTZ00443 135 ALG 137

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 68163437 194 TLVLFYTPWCRFSASLAPHFNSLPRAF---PTLGFLALDASQ-HSSLSTRFGTVAVPNILLFQ--GAKPMArFNhTDRTL 267
Cdd:cd02998  21 VLVEFYAPWCGHCKNLAPEYEKLAAVFaneDDVVIAKVDADEaNKDLAKKYGVSGFPTLKFFPkgSTEPVK-YE-GGRDL 98

                ....*..
gi 68163437 268 ETLKIFI 274
Cdd:cd02998  99 EDLVKFV 105

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 68163437 181 DLMD-FLNPNGSDCTLVLFYTPWCRFSASLAPHFNSLPRAFPTLGFLA----LDASQHSSLSTRFGTVAVPNILLFQG 253
Cdd:cd03000   4 DLDDsFKDVRKEDIWLVDFYAPWCGHCKKLEPVWNEVGAELKSSGSPVrvgkLDATAYSSIASEFGVRGYPTIKLLKG 81

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 68163437 180 QDLMDFLNPNGSDCTLVLFYTPWCRFSASLAPHFNSLPR-AFPTLGFLALDASQHSSLSTRFGTVAVPNILLFQGAKPMA 258
Cdd:cd02984   3 EEFEELLKSDASKLLVLHFWAPWAEPCKQMNQVFEELAKeAFPSVLFLSIEAEELPEISEKFEITAVPTFVFFRNGTIVD 82

                .
gi 68163437 259 R 259
Cdd:cd02984  83 R 83

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 68163437 195 LVLFYTPWCRFSASLAPHFNSLPRAF---PTLGFLALDASQ---HSSLSTRfgtvAVPNILLFQ--GAKPMARFNhTDRT 266
Cdd:cd02995  22 LVEFYAPWCGHCKALAPIYEELAEKLkgdDNVVIAKMDATAndvPSEFVVD----GFPTILFFPagDKSNPIKYE-GDRT 96

                ....*...
gi 68163437 267 LETLKIFI 274
Cdd:cd02995  97 LEDLIKFI 104

disulphide isomerase; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 68163437  184 DFLNPNgsDCTLVLFYTPWCRFSASLAPHFNS----LPRAFPTLGFLALDASQHSSLSTRFGTVAVPNILLFQGAKP 256
Cdd:PTZ00102  44 KFITEN--EIVLVKFYAPWCGHCKRLAPEYKKaakmLKEKKSEIVLASVDATEEMELAQEFGVRGYPTIKFFNKGNP 118

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        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 68163437 194 TLVLFYTPWCRFSASLAPHFNSLPRAFPTLG---FLALDA--SQHSSLSTRFGTVAVPNILLFQGAKPMARFN 261
Cdd:cd02997  20 VLVMFYAPWCGHCKKMKPEFTKAATELKEDGkgvLAAVDCtkPEHDALKEEYNVKGFPTFKYFENGKFVEKYE 92

thioredoxin; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 68163437  190 GSDCTLVLFYTPWCRFSASLAPHFNSLPRAFPTLGFLALDASQHSSLSTRFGTVAVPNILLFQGAKPMARF 260
Cdd:PTZ00051  17 QNELVIVDFYAEWCGPCKRIAPFYEECSKEYTKMVFVKVDVDELSEVAEKENITSMPTFKVFKNGSVVDTL 87

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 68163437 194 TLVLFYTPWCRFSASLAPHFNSLPRAFPTLGFLAL---DASQHSSLSTRFGTVAVPNILLFQGAKPMAR 259
Cdd:cd03002  21 TLVEFYAPWCGHCKNLKPEYAKAAKELDGLVQVAAvdcDEDKNKPLCGKYGVQGFPTLKVFRPPKKASK 89

ybbN protein family; ybbN is a hypothetical protein containing a redox-inactive TRX-like domain. Its gene has been sequenced from several gammaproteobacteria and actinobacteria.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 68163437 195 LVLFYTPWCRFSASLAPHFNSLPRAFPTLGFLA-LDASQHSSLSTRFGTVAVPNILLFQGAKPMARFN 261
Cdd:cd02956  16 VVDFWAPRSPPSKELLPLLERLAEEYQGQFVLAkVNCDAQPQIAQQFGVQALPTVYLFAAGQPVDGFQ 83