TMX2 family; composed of proteins similar to human TMX2, a 372-amino acid TRX-related transmembrane protein, identified and characterized through the cloning of its cDNA from a human fetal library. It contains a TRX domain but the redox active CXXC motif is replaced with SXXC. Sequence analysis predicts that TMX2 may be a Type I membrane protein, with its C-terminal half protruding on the luminal side of the endoplasmic reticulum (ER). In addition to the TRX domain, transmembrane region and ER-retention signal, TMX2 also contains a Myb DNA-binding domain repeat signature and a dileucine motif in the tail.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91085249  96 DFLMGIIYGIIFILGALLFPEPTYSGPDNVIYFRGMQgLDEELARSRDGYWLVTFYTVWNPACVNFAPVFAKLSTEYHLE 175
Cdd:cd02962   1 DIRLGLLYLLLCIVVYLLAPQPLYMGPEHIKYFTPKT-LEEELERDKRVTWLVEFFTTWSPECVNFAPVFAELSLKYNNN 79

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 91085249 176 NFKFGKIDVGRYPDAAQKYRVNDSSLSKQLPTTILFKEGKEVVRRPA-IDSKGNILKFFFSSENVKGAFDLNN 247
Cdd:cd02962  80 NLKFGKIDIGRFPNVAEKFRVSTSPLSKQLPTIILFQGGKEVARRPYyNDSKGRAVPFTFSKENVIRHFDLDR 152

TMX2 family; composed of proteins similar to human TMX2, a 372-amino acid TRX-related transmembrane protein, identified and characterized through the cloning of its cDNA from a human fetal library. It contains a TRX domain but the redox active CXXC motif is replaced with SXXC. Sequence analysis predicts that TMX2 may be a Type I membrane protein, with its C-terminal half protruding on the luminal side of the endoplasmic reticulum (ER). In addition to the TRX domain, transmembrane region and ER-retention signal, TMX2 also contains a Myb DNA-binding domain repeat signature and a dileucine motif in the tail.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91085249  96 DFLMGIIYGIIFILGALLFPEPTYSGPDNVIYFRGMQgLDEELARSRDGYWLVTFYTVWNPACVNFAPVFAKLSTEYHLE 175
Cdd:cd02962   1 DIRLGLLYLLLCIVVYLLAPQPLYMGPEHIKYFTPKT-LEEELERDKRVTWLVEFFTTWSPECVNFAPVFAELSLKYNNN 79

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 91085249 176 NFKFGKIDVGRYPDAAQKYRVNDSSLSKQLPTTILFKEGKEVVRRPA-IDSKGNILKFFFSSENVKGAFDLNN 247
Cdd:cd02962  80 NLKFGKIDIGRFPNVAEKFRVSTSPLSKQLPTIILFQGGKEVARRPYyNDSKGRAVPFTFSKENVIRHFDLDR 152

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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91085249   134 LDEELARSrDGYWLVTFYTVWNPACVNFAPVFAKLSTEYHlENFKFGKIDVGRYPDAAQKYRVndSSLskqlPTTILFKE 213
Cdd:TIGR01068   6 FDETIASS-DKPVLVDFWAPWCGPCKMIAPILEELAKEYE-GKVKFVKLNVDENPDIAAKYGI--RSI----PTLLLFKN 77

                          90       100
                  ....*....|....*....|
gi 91085249   214 GKEVVRRPAIDSKGNILKFF 233
Cdd:TIGR01068  78 GKEVDRSVGALPKAALKQLI 97

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 91085249   135 DEELArSRDGYWLVTFYTVWNPACVNFAPVFAKLSTEYHlENFKFGKIDVGRYPDAAQKYRVndsslsKQLPTTILFKEG 214
Cdd:pfam00085  11 DEVVQ-KSSKPVLVDFYAPWCGPCKMLAPEYEELAQEYK-GNVVFAKVDVDENPDLASKYGV------RGYPTLIFFKNG 82

                  ...
gi 91085249   215 KEV 217
Cdd:pfam00085  83 QPV 85

TMX2 family; composed of proteins similar to human TMX2, a 372-amino acid TRX-related transmembrane protein, identified and characterized through the cloning of its cDNA from a human fetal library. It contains a TRX domain but the redox active CXXC motif is replaced with SXXC. Sequence analysis predicts that TMX2 may be a Type I membrane protein, with its C-terminal half protruding on the luminal side of the endoplasmic reticulum (ER). In addition to the TRX domain, transmembrane region and ER-retention signal, TMX2 also contains a Myb DNA-binding domain repeat signature and a dileucine motif in the tail.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91085249  96 DFLMGIIYGIIFILGALLFPEPTYSGPDNVIYFRGMQgLDEELARSRDGYWLVTFYTVWNPACVNFAPVFAKLSTEYHLE 175
Cdd:cd02962   1 DIRLGLLYLLLCIVVYLLAPQPLYMGPEHIKYFTPKT-LEEELERDKRVTWLVEFFTTWSPECVNFAPVFAELSLKYNNN 79

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 91085249 176 NFKFGKIDVGRYPDAAQKYRVNDSSLSKQLPTTILFKEGKEVVRRPA-IDSKGNILKFFFSSENVKGAFDLNN 247
Cdd:cd02962  80 NLKFGKIDIGRFPNVAEKFRVSTSPLSKQLPTIILFQGGKEVARRPYyNDSKGRAVPFTFSKENVIRHFDLDR 152

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 91085249 147 LVTFYTVWNPACVNFAPVFAKLSTEYhlENFKFGKIDVGRYPDAAQKYRVndsslsKQLPTTILFKEGKEVVRRPAIDSK 226
Cdd:cd02947  14 VVDFWAPWCGPCKAIAPVLEELAEEY--PKVKFVKVDVDENPELAEEYGV------RSIPTFLFFKNGKEVDRVVGADPK 85

                ....*..
gi 91085249 227 GNILKFF 233
Cdd:cd02947  86 EELEEFL 92

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 91085249 135 DEELARSRDgyWLVTFYTVWNPACVNFAPVFAKLSTEYHL-ENFKFGKIDVGRYPDAAQKYRVndsslsKQLPTTILFKE 213
Cdd:cd02961   9 DELVKDSKD--VLVEFYAPWCGHCKALAPEYEKLAKELKGdGKVVVAKVDCTANNDLCSEYGV------RGYPTIKLFPN 80

                ...
gi 91085249 214 GKE 216
Cdd:cd02961  81 GSK 83

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 91085249   135 DEELArSRDGYWLVTFYTVWNPACVNFAPVFAKLSTEYHlENFKFGKIDVGRYPDAAQKYRVndsslsKQLPTTILFKEG 214
Cdd:pfam00085  11 DEVVQ-KSSKPVLVDFYAPWCGPCKMLAPEYEELAQEYK-GNVVFAKVDVDENPDLASKYGV------RGYPTLIFFKNG 82

                  ...
gi 91085249   215 KEV 217
Cdd:pfam00085  83 QPV 85

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        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91085249 132 QGLDEELARSRDGYWLVTFYTVWNPACVNFAPVFAKLSTEYHLEnFKFGKIDVGRYPDAAQKYRVndsslsKQLPTTILF 211
Cdd:cd02956   1 QNFQQVLQESTQVPVVVDFWAPRSPPSKELLPLLERLAEEYQGQ-FVLAKVNCDAQPQIAQQFGV------QALPTVYLF 73

                ....*.
gi 91085249 212 KEGKEV 217
Cdd:cd02956  74 AAGQPV 79

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        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91085249 133 GLDEELARSR-DGYWLVTFYTVWNPACVNFAPVFAKLSTEY--HLENFKFGKIDVGRYPDAAQKYRVndsslsKQLPTTI 209
Cdd:cd03000   4 DLDDSFKDVRkEDIWLVDFYAPWCGHCKKLEPVWNEVGAELksSGSPVRVGKLDATAYSSIASEFGV------RGYPTIK 77

                ...
gi 91085249 210 LFK 212
Cdd:cd03000  78 LLK 80

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 91085249 147 LVTFYTVWNPACVNFAPVFAKLSTEYHlENFKFGKIDVGRYPDAAQKYRVNdsslskQLPTTILFKEGKEVVR 219
Cdd:cd02984  18 VLHFWAPWAEPCKQMNQVFEELAKEAF-PSVLFLSIEAEELPEISEKFEIT------AVPTFVFFRNGTIVDR 83

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 91085249 144 GYWLVTFYTVWNPACVNFAPVFAKLSTEYHLENFKFGKIDVGRYPDAAQKYRVNdsslskQLPTTILFKEGkeVVRR 220
Cdd:cd02994  17 GEWMIEFYAPWCPACQQLQPEWEEFADWSDDLGINVAKVDVTQEPGLSGRFFVT------ALPTIYHAKDG--VFRR 85

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 91085249 147 LVTFYTVWNPACVNFAPVFAKLSTEYHLENFK-----FGKIDVGRYPDAAQKYRVNdsslskQLPTTILFKEG 214
Cdd:cd02996  22 LVNFYADWCRFSQMLHPIFEEAAAKIKEEFPDagkvvWGKVDCDKESDIADRYRIN------KYPTLKLFRNG 88

disulphide isomerase; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 91085249  147 LVTFYTVWNPACVNFAPVFAKLSTEYHLEN--FKFGKIDVGRYPDAAQKYRVndsslsKQLPTTILFKEGKEV 217
Cdd:PTZ00102  53 LVKFYAPWCGHCKRLAPEYKKAAKMLKEKKseIVLASVDATEEMELAQEFGV------RGYPTIKFFNKGNPV 119

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        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 91085249 143 DGYWLVTFYTVWNPACVNFAPVFAKLSTEyhLEN-FKFGKIDVGRYPDAAQKYRVndsslsKQLPTTILFKEGKE 216
Cdd:cd03001  18 DDVWLVEFYAPWCGHCKNLAPEWKKAAKA--LKGiVKVGAVDADVHQSLAQQYGV------RGFPTIKVFGAGKN 84