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 40254947  37 SRVQPMTASNWTLVMEGEWMLKFYAPWCPSCQQTDSEWEAFAKNGEILQISVGKVDVIQEPGLSGRFFVTTLPAFFHAKD 116
Cdd:cd02994   1 SNVVELTDSNWTLVLEGEWMIEFYAPWCPACQQLQPEWEEFADWSDDLGINVAKVDVTQEPGLSGRFFVTALPTIYHAKD 80

                        90       100
                ....*....|....*....|.
gi 40254947 117 GIFRRYRGPGIFEDLQNYILE 137
Cdd:cd02994  81 GVFRRYQGPRDKEDLISFIEE 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 40254947  37 SRVQPMTASNWTLVMEGEWMLKFYAPWCPSCQQTDSEWEAFAKNGEILQISVGKVDVIQEPGLSGRFFVTTLPAFFHAKD 116
Cdd:cd02994   1 SNVVELTDSNWTLVLEGEWMIEFYAPWCPACQQLQPEWEEFADWSDDLGINVAKVDVTQEPGLSGRFFVTALPTIYHAKD 80

                        90       100
                ....*....|....*....|.
gi 40254947 117 GIFRRYRGPGIFEDLQNYILE 137
Cdd:cd02994  81 GVFRRYQGPRDKEDLISFIEE 101

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

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 40254947  56 MLKFYAPWCPSCQQTDSEWEAFAK--NGeilQISVGKVDVIQEPGLSGRFFVTTLPAFFHAKDG 117
Cdd:COG3118  22 LVDFWAPWCGPCKMLAPVLEELAAeyGG---KVKFVKVDVDENPELAAQFGVRSIPTLLLFKDG 82

thioredoxin; Several proteins, such as protein disulfide isomerase, have two or more copies of a domain closely related to thioredoxin. This model is designed to recognize authentic thioredoxin, a small protein that should be hit exactly once by this model. Any protein that hits once with a score greater than the second (per domain) trusted cutoff may be taken as thioredoxin. [Energy metabolism, Electron transport]

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 40254947    59 FYAPWCPSCQQTDSEWEAFAKNGEiLQISVGKVDVIQEPGLSGRFFVTTLPAFFHAKDG 117
Cdd:TIGR01068  21 FWAPWCGPCKMIAPILEELAKEYE-GKVKFVKLNVDENPDIAAKYGIRSIPTLLLFKNG 78

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 40254947  37 SRVQPMTASNWTLVMEGEWMLKFYAPWCPSCQQTDSEWEAFAKNGEILQISVGKVDVIQEPGLSGRFFVTTLPAFFHAKD 116
Cdd:cd02994   1 SNVVELTDSNWTLVLEGEWMIEFYAPWCPACQQLQPEWEEFADWSDDLGINVAKVDVTQEPGLSGRFFVTALPTIYHAKD 80

                        90       100
                ....*....|....*....|.
gi 40254947 117 GIFRRYRGPGIFEDLQNYILE 137
Cdd:cd02994  81 GVFRRYQGPRDKEDLISFIEE 101

Thioredoxin domain-containing protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 40254947   35 EQSRVQPMTASNW-------TLVMEGEWMLKFYAPWCPSCQQTDSEWEAFAK--NGeilQISVGKVDVIQEPGLSGRFFV 105
Cdd:PTZ00443  28 DANALVLLNDKNFekltqasTGATTGPWFVKFYAPWCSHCRKMAPAWERLAKalKG---QVNVADLDATRALNLAKRFAI 104

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 40254947  106 TTLPAFFHAKDGIFRRYR-GPGIFEDLQNYILEKKWQSVepltGWKSPASLTMSGMAGLFSISGKIWHLHNYFTVTLGip 184
Cdd:PTZ00443 105 KGYPTLLLFDKGKMYQYEgGDRSTEKLAAFALGDFKKAL----GAPVPAPLSFFALTIDFFVSGTNEALRIYDAAFAG-- 178

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|.
gi 40254947  185 awcsyvFFVIATLVF--GLFMGLVLVVI------SECFYVPLPRHLSERSE 227
Cdd:PTZ00443 179 ------FFTISSFAFlfGILMGLMIALFafskgnSTAHANKKPKVLNARKK 223

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 40254947  39 VQPMTASNWTL-VMEGEWMLKFYAPWCPSCQQTDSEWEAFAK--NGEILQISVGKVDVIQEPGLSGRFFVTTLPAFFHAK 115
Cdd:cd03005   2 VLELTEDNFDHhIAEGNHFVKFFAPWCGHCKRLAPTWEQLAKkfNNENPSVKIAKVDCTQHRELCSEFQVRGYPTLLLFK 81

                        90       100
                ....*....|....*....|.
gi 40254947 116 DGI-FRRYRGPGIFEDLQNYI 135
Cdd:cd03005  82 DGEkVDKYKGTRDLDSLKEFV 102

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

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 40254947  56 MLKFYAPWCPSCQQTDSEWEAFAK--NGeilQISVGKVDVIQEPGLSGRFFVTTLPAFFHAKDG 117
Cdd:COG3118  22 LVDFWAPWCGPCKMLAPVLEELAAeyGG---KVKFVKVDVDENPELAAQFGVRSIPTLLLFKDG 82

PDIa family, P5 subfamily; composed of eukaryotic proteins similar to human P5, a PDI-related protein with a domain structure of aa'b (where a and a' are redox active TRX domains and b is a redox inactive TRX-like domain). Like PDI, P5 is located in the endoplasmic reticulum (ER) and displays both isomerase and chaperone activities, which are independent of each other. Compared to PDI, the isomerase and chaperone activities of P5 are lower. The first cysteine in the CXXC motif of both redox active domains in P5 is necessary for isomerase activity. The P5 gene was first isolated as an amplified gene from a hydroxyurea-resistant hamster cell line. The zebrafish P5 homolog has been implicated to play a critical role in establishing left/right asymmetries in the embryonic midline. Some members of this subfamily are P5-like proteins containing only one redox active TRX domain.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 40254947  55 WMLKFYAPWCPSCQQTDSEWEAFAKN--GeilQISVGKVDVIQEPGLSGRFFVTTLP 109
Cdd:cd03001  21 WLVEFYAPWCGHCKNLAPEWKKAAKAlkG---IVKVGAVDADVHQSLAQQYGVRGFP 74

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        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 40254947  56 MLKFYAPWCPSCQQTDSEWEAFAKngEILQISVGKVDVIQEPGL---SGRFFVTTLPAFFHAKDGIFRRY 122
Cdd:cd01659   1 LVLFYAPWCPFCQALRPVLAELAL--LNKGVKFEAVDVDEDPALekeLKRYGVGGVPTLVVFGPGIGVKY 68

thioredoxin; Several proteins, such as protein disulfide isomerase, have two or more copies of a domain closely related to thioredoxin. This model is designed to recognize authentic thioredoxin, a small protein that should be hit exactly once by this model. Any protein that hits once with a score greater than the second (per domain) trusted cutoff may be taken as thioredoxin. [Energy metabolism, Electron transport]

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 40254947    59 FYAPWCPSCQQTDSEWEAFAKNGEiLQISVGKVDVIQEPGLSGRFFVTTLPAFFHAKDG 117
Cdd:TIGR01068  21 FWAPWCGPCKMIAPILEELAKEYE-GKVKFVKLNVDENPDIAAKYGIRSIPTLLLFKNG 78

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 40254947  58 KFYAPWCPSCQQTDSEWE----AFAKNGEILqisVGKVDVIQEPG-LSGRFFVTTLP--AFFHAKDGIFRRYRGPGIFED 130
Cdd:cd02998  24 EFYAPWCGHCKNLAPEYEklaaVFANEDDVV---IAKVDADEANKdLAKKYGVSGFPtlKFFPKGSTEPVKYEGGRDLED 100

                ....*
gi 40254947 131 LQNYI 135
Cdd:cd02998 101 LVKFV 105

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        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 40254947  48 TLVMegewmlkFYAPWCPSCQQTDSEweaFAKNGEILQ----ISVGKVDV--IQEPGLSGRFFVTTLPAFFHAKDGIFRR 121
Cdd:cd02997  20 VLVM-------FYAPWCGHCKKMKPE---FTKAATELKedgkGVLAAVDCtkPEHDALKEEYNVKGFPTFKYFENGKFVE 89

                        90
                ....*....|....*
gi 40254947 122 -YRGPGIFEDLQNYI 135
Cdd:cd02997  90 kYEGERTAEDIIEFM 104

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
                ....*....|....*....|....*
gi 40254947  56 MLKFYAPWCPSCQQTDSEWEAFAKN 80
Cdd:cd03002  22 LVEFYAPWCGHCKNLKPEYAKAAKE 46

thioredoxin; Provisional

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 40254947   59 FYAPWCPSCQQTDSEWEAFAKngEILQISVGKVDVIQEPGLSGRFFVTTLPAFFHAKDG 117
Cdd:PTZ00051  25 FYAEWCGPCKRIAPFYEECSK--EYTKMVFVKVDVDELSEVAEKENITSMPTFKVFKNG 81