disulphide isomerase; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 285812642 404 VTQLPTFFMFKDGDPISYvfpgystTEMRNIDAIMDWVKKYSNPLVTEVDSSNLKKLI--SFQTKSYSDLA 472
Cdd:PTZ00102 104 VRGYPTIKFFNKGNPVNY-------SGGRTADGIVSWIKKLTGPAVTEVESASEIKLIakKIFVAFYGEYT 167

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 285812642  35 EPLNPTNFKEELSKG-LHIIDFYSPYCPHCKHLAPVWMETWEEFKEESKtlnITFSQVNCIESADLCGDENIEYFPEIRL 113
Cdd:cd02961    1 VELTDDNFDELVKDSkDVLVEFYAPWCGHCKALAPEYEKLAKELKGDGK---VVVAKVDCTANNDLCSEYGVRGYPTIKL 77

                         90       100
                 ....*....|....*....|....
gi 285812642 114 YNPSGYIKSFTETPRTKESLIAFA 137
Cdd:cd02961   78 FPNGSKEPVKYEGPRTLESLVEFI 101

disulphide isomerase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 285812642   7 RLVVTFFSCITFLLKFTIAAAEPPEGFPE---PLNPTNFKEELSKGLHII-DFYSPYCPHCKHLAPVWMETWEEFKEESK 82
Cdd:PTZ00102   4 RSILSSLFLLLILLAFAVFGSAEEHFISEhvtVLTDSTFDKFITENEIVLvKFYAPWCGHCKRLAPEYKKAAKMLKEKKS 83

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|..
gi 285812642  83 tlNITFSQVNCIESADLCGDENIEYFPEIRLYNPSGYIKsFTETpRTKESLI 134
Cdd:PTZ00102  84 --EIVLASVDATEEMELAQEFGVRGYPTIKFFNKGNPVN-YSGG-RTADGIV 131

disulphide isomerase; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 285812642 404 VTQLPTFFMFKDGDPISYvfpgystTEMRNIDAIMDWVKKYSNPLVTEVDSSNLKKLI--SFQTKSYSDLA 472
Cdd:PTZ00102 104 VRGYPTIKFFNKGNPVNY-------SGGRTADGIVSWIKKLTGPAVTEVESASEIKLIakKIFVAFYGEYT 167

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 285812642  35 EPLNPTNFKEELSKG-LHIIDFYSPYCPHCKHLAPVWMETWEEFKEESKtlnITFSQVNCIESADLCGDENIEYFPEIRL 113
Cdd:cd02961    1 VELTDDNFDELVKDSkDVLVEFYAPWCGHCKALAPEYEKLAKELKGDGK---VVVAKVDCTANNDLCSEYGVRGYPTIKL 77

                         90       100
                 ....*....|....*....|....
gi 285812642 114 YNPSGYIKSFTETPRTKESLIAFA 137
Cdd:cd02961   78 FPNGSKEPVKYEGPRTLESLVEFI 101

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 285812642  37 LNPTNFKEELSKGLHIIDFYSPYCPHCKHLAPVWMETWEEFKEESKTLNItfSQVNCIESADLCGDENIEYFPEIRLYNP 116
Cdd:cd03005    5 LTEDNFDHHIAEGNHFVKFFAPWCGHCKRLAPTWEQLAKKFNNENPSVKI--AKVDCTQHRELCSEFQVRGYPTLLLFKD 82

                         90       100
                 ....*....|....*....|
gi 285812642 117 SGYIKSFtETPRTKESLIAF 136
Cdd:cd03005   83 GEKVDKY-KGTRDLDSLKEF 101

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        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 285812642  37 LNPTNFKEEL--SKGLHIIDFYSPYCPHCKHLAPvwmetweEFKEESKTLN--ITFSQVNCIESA--DLCGDENIEYFPE 110
Cdd:cd03002    5 LTPKNFDKVVhnTNYTTLVEFYAPWCGHCKNLKP-------EYAKAAKELDglVQVAAVDCDEDKnkPLCGKYGVQGFPT 77

                         90       100       110
                 ....*....|....*....|....*....|.
gi 285812642 111 IRLYNPSGYIKSFTET----PRTKESLIAFA 137
Cdd:cd03002   78 LKVFRPPKKASKHAVEdyngERSAKAIVDFV 108

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 285812642  32 GFPEPLNPTNFKEELsKGLHIIDFYSPYCPHCKHLAPVwmetWEEFKEESKTLNITFSQVNCIESADLCGDENIEYFPEI 111
Cdd:cd02994    1 SNVVELTDSNWTLVL-EGEWMIEFYAPWCPACQQLQPE----WEEFADWSDDLGINVAKVDVTQEPGLSGRFFVTALPTI 75

                         90       100       110
                 ....*....|....*....|....*....|...
gi 285812642 112 --------RLYnpsgyiksftETPRTKESLIAF 136
Cdd:cd02994   76 yhakdgvfRRY----------QGPRDKEDLISF 98

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 285812642  37 LNPTNFKEELSKGLHI-IDFYSPYCPHCKHLAPVWMETWEEFKEESKtlnITFSQVNC-IESADLCGDE-NIEYFPEIRL 113
Cdd:cd02997    5 LTDEDFRKFLKKEKHVlVMFYAPWCGHCKKMKPEFTKAATELKEDGK---GVLAAVDCtKPEHDALKEEyNVKGFPTFKY 81

                         90       100
                 ....*....|....*....|...
gi 285812642 114 YNpSGYIKSFTETPRTKESLIAF 136
Cdd:cd02997   82 FE-NGKFVEKYEGERTAEDIIEF 103

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 285812642   37 LNPTNFKEELSKGLHII-DFYSPYCPHCKHLAPVWMETWEEFKEESKtlNITFSQVNCIESADLCGDENIEYFPEIRLYN 115
Cdd:TIGR01130   6 LTKDNFDDFIKSHEFVLvEFYAPWCGHCKSLAPEYEKAADELKKKGP--PIKLAKVDATEEKDLAQKYGVSGYPTLKIFR 83

                          90       100
                  ....*....|....*....|....*.
gi 285812642  116 PSGYIKSFTETPRTKESLIAFARRES 141
Cdd:TIGR01130  84 NGEDSVSDYNGPRDADGIVKYMKKQS 109

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 285812642  41 NFKEELSK-GLHIIDFYSPYCPHCKHLAPVwmetWEEFKEESKtlNITFSQVNCIESADLCGDENIEYFPEIRLY 114
Cdd:cd02947    2 EFEELIKSaKPVVVDFWAPWCGPCKAIAPV----LEELAEEYP--KVKFVKVDVDENPELAEEYGVRSIPTFLFF 70

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 285812642  53 IDFYSPYCPHCKHLAPVWMETWEEFKEESktlNITFSQVNcIESADLCGDENIEYFPEIRLYnPSGYIK---SFTEtPRT 129
Cdd:cd02995   23 VEFYAPWCGHCKALAPIYEELAEKLKGDD---NVVIAKMD-ATANDVPSEFVVDGFPTILFF-PAGDKSnpiKYEG-DRT 96

                 ....*..
gi 285812642 130 KESLIAF 136
Cdd:cd02995   97 LEDLIKF 103

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 285812642  34 PEPLNPTNFKEEL--SKGLHIIDFYSPYCPHCKHLAPVWMETWEEFKEEsktlnITFSQVNCIESADLCGDENIEYFPEI 111
Cdd:COG3118    2 VVELTDENFEEEVleSDKPVLVDFWAPWCGPCKMLAPVLEELAAEYGGK-----VKFVKVDVDENPELAAQFGVRSIPTL 76

                 ...
gi 285812642 112 RLY 114
Cdd:COG3118   77 LLF 79

thioredoxin; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 285812642  42 FKEELSKG-LHIIDFYSPYCPHCKHLAPVWMETWEEFKeesktlNITFSQVNCIESADLCGDENIEYFPEIRLY 114
Cdd:PTZ00051  11 FESTLSQNeLVIVDFYAEWCGPCKRIAPFYEECSKEYT------KMVFVKVDVDELSEVAEKENITSMPTFKVF 78

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 285812642  47 SKGLHIIDFYSPYCPHCKHLAPVWMETWEEFKEESKTLN-ITFSQVNCIESADLCGDENIEYFPEIRLYNPSGYIKSFTE 125
Cdd:cd02996   17 SAELVLVNFYADWCRFSQMLHPIFEEAAAKIKEEFPDAGkVVWGKVDCDKESDIADRYRINKYPTLKLFRNGMMMKREYR 96

                         90
                 ....*....|.
gi 285812642 126 TPRTKESLIAF 136
Cdd:cd02996   97 GQRSVEALAEF 107

Thiol-disulfide isomerase or thioredoxin [Posttranslational modification, protein turnover, chaperones];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 285812642  44 EELSKGLHIIDFYSPYCPHCKHLAPVWMETWEEFK---------EES--------KTLNITFSQVNcIESADLCGDENIE 106
Cdd:COG0526   24 ADLKGKPVLVNFWATWCPPCRAEMPVLKELAEEYGgvvfvgvdvDENpeavkaflKELGLPYPVLL-DPDGELAKAYGVR 102

                         90       100       110
                 ....*....|....*....|....*....|...
gi 285812642 107 YFPEIRLYNPSGYIKSFTETPRTKESLIAFARR 139
Cdd:COG0526  103 GIPTTVLIDKDGKIVARHVGPLSPEELEEALEK 135