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 392920290  46 EDFtEKVIQSSVPVIVDFHAEWCGPCQALGPRLEEkVNGRQGSVLLAKINVDHAGELAMDYGISAVPTVFAFKNGEKISG 125
Cdd:cd02947    1 EEF-EELIKSAKPVVVDFWAPWCGPCKAIAPVLEE-LAEEYPKVKFVKVDVDENPELAEEYGVRSIPTFLFFKNGKEVDR 78

                         90
                 ....*....|....*
gi 392920290 126 FSGVLDDEQLDDFIE 140
Cdd:cd02947   79 VVGADPKEELEEFLE 93

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 392920290   44 SVEDFTEKVIQSSVPVIVDFHAEWCGPCQALGPRLEEKVNGRQGSVLLAKINVDHAGELAMDYGISAVPTVFAFKNGEKI 123
Cdd:pfam00085   6 TDANFDEVVQKSSKPVLVDFYAPWCGPCKMLAPEYEELAQEYKGNVVFAKVDVDENPDLASKYGVRGYPTLIFFKNGQPV 85

                          90
                  ....*....|....*...
gi 392920290  124 SGFSGVLDDEQLDDFIED 141
Cdd:pfam00085  86 DDYVGARPKDALAAFLKA 103

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 392920290  46 EDFtEKVIQSSVPVIVDFHAEWCGPCQALGPRLEEkVNGRQGSVLLAKINVDHAGELAMDYGISAVPTVFAFKNGEKISG 125
Cdd:cd02947    1 EEF-EELIKSAKPVVVDFWAPWCGPCKAIAPVLEE-LAEEYPKVKFVKVDVDENPELAEEYGVRSIPTFLFFKNGKEVDR 78

                         90
                 ....*....|....*
gi 392920290 126 FSGVLDDEQLDDFIE 140
Cdd:cd02947   79 VVGADPKEELEEFLE 93

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 392920290   44 SVEDFTEKVIQSSVPVIVDFHAEWCGPCQALGPRLEEKVNGRQGSVLLAKINVDHAGELAMDYGISAVPTVFAFKNGEKI 123
Cdd:pfam00085   6 TDANFDEVVQKSSKPVLVDFYAPWCGPCKMLAPEYEELAQEYKGNVVFAKVDVDENPDLASKYGVRGYPTLIFFKNGQPV 85

                          90
                  ....*....|....*...
gi 392920290  124 SGFSGVLDDEQLDDFIED 141
Cdd:pfam00085  86 DDYVGARPKDALAAFLKA 103

thioredoxin 2; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392920290  36 GASVFD---IDSVEDFTEKVIQSSVPVIVDFHAEWCGPCQALGPRLEEKVNGRQGSVLLAKINVDHAGELAMDYGISAVP 112
Cdd:PRK10996  29 GHDLFDgevINATGETLDKLLQDDLPVVIDFWAPWCGPCRNFAPIFEDVAAERSGKVRFVKVNTEAERELSARFRIRSIP 108

                         90       100       110
                 ....*....|....*....|....*....|.
gi 392920290 113 TVFAFKNGEKISGFSGVLDDEQLDDFIEDVL 143
Cdd:PRK10996 109 TIMIFKNGQVVDMLNGAVPKAPFDSWLNEAL 139

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 392920290  46 EDFtEKVIQSSVPVIVDFHAEWCGPCQALGPRLEE---KVNGrQGSVLLAKINVDHAGELAMDYGISAVPTVFAFKNG-E 121
Cdd:cd02961    6 DNF-DELVKDSKDVLVEFYAPWCGHCKALAPEYEKlakELKG-DGKVVVAKVDCTANNDLCSEYGVRGYPTIKLFPNGsK 83

                         90
                 ....*....|....*...
gi 392920290 122 KISGFSGVLDDEQLDDFI 139
Cdd:cd02961   84 EPVKYEGPRTLESLVEFI 101

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392920290  44 SVEDFTEKviqssvPVIVDFHAEWCGPCQALGPRLEEkVNGRQGSVLLAKINV----------------------DHAGE 101
Cdd:COG0526   22 SLADLKGK------PVLVNFWATWCPPCRAEMPVLKE-LAEEYGGVVFVGVDVdenpeavkaflkelglpypvllDPDGE 94

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 392920290 102 LAMDYGISAVPTVFAF-KNGEKISGFSGVLDDEQLDDFIEDVLAA 145
Cdd:COG0526   95 LAKAYGVRGIPTTVLIdKDGKIVARHVGPLSPEELEEALEKLLAK 139

disulphide isomerase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392920290  33 FSHGASVFDIDSVEDFT----EKVIQSSVPVIVDFHAEWCGPCQALGPRLEEKVN--GRQGS-VLLAKINVDHAGELAMD 105
Cdd:PTZ00102  22 FGSAEEHFISEHVTVLTdstfDKFITENEIVLVKFYAPWCGHCKRLAPEYKKAAKmlKEKKSeIVLASVDATEEMELAQE 101

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 392920290 106 YGISAVPTVFAFKNGEKISgFSGVLDDEQLDDFIEDVL 143
Cdd:PTZ00102 102 FGVRGYPTIKFFNKGNPVN-YSGGRTADGIVSWIKKLT 138

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392920290  43 DSVE----DFTEKVIQSSVPVIVDFHAEWCGPCQALGPRLEEKVNGRQGSVLLAKINVDHAGELAMDYGISAVPTVFAFK 118
Cdd:cd03001    1 DVVEltdsNFDKKVLNSDDVWLVEFYAPWCGHCKNLAPEWKKAAKALKGIVKVGAVDADVHQSLAQQYGVRGFPTIKVFG 80

                 ....
gi 392920290 119 NGEK 122
Cdd:cd03001   81 AGKN 84

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 392920290  46 EDFTEKViqSSVPVIVDFHAEWCGPCQALGPRLEE---KVNGRQGSVLLAKINVDHAGELAMDYGISAVPTVFAFKNGEK 122
Cdd:cd03005    8 DNFDHHI--AEGNHFVKFFAPWCGHCKRLAPTWEQlakKFNNENPSVKIAKVDCTQHRELCSEFQVRGYPTLLLFKDGEK 85

                         90
                 ....*....|....*..
gi 392920290 123 ISGFSGVLDDEQLDDFI 139
Cdd:cd03005   86 VDKYKGTRDLDSLKEFV 102

disulphide isomerase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392920290  48 FTEKVIQSSVPVIVDFHAEWCGPCQALGPRLEE--KVNGRQGSVLLAKINVDhAGELAM-DYGISAVPTVFAFKNGEKIS 124
Cdd:PTZ00102 367 FEEIVFKSDKDVLLEIYAPWCGHCKNLEPVYNElgEKYKDNDSIIVAKMNGT-ANETPLeEFSWSAFPTILFVKAGERTP 445

                         90
                 ....*....|....*..
gi 392920290 125 -GFSGVLDDEQLDDFIE 140
Cdd:PTZ00102 446 iPYEGERTVEGFKEFVN 462

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 392920290  46 EDFTEKVIQSSVPVIVDFHAEWCGPCQALGPRLEE--KVNGRQGSVLLAKINVDhAGELAMDYGISAVPTVFAFKNGEK- 122
Cdd:cd02995    8 KNFDEVVLDSDKDVLVEFYAPWCGHCKALAPIYEElaEKLKGDDNVVIAKMDAT-ANDVPSEFVVDGFPTILFFPAGDKs 86

                         90
                 ....*....|....*....
gi 392920290 123 --ISgFSGVLDDEQLDDFI 139
Cdd:cd02995   87 npIK-YEGDRTLEDLIKFI 104

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 392920290  50 EKVIQSSVPVIVDFHAEWCGPCQALGPRLEE---KVNGR---QGSVLLAKINVDHAGELAMDYGISAVPTVFAFKNGE 121
Cdd:cd02996   12 DDILQSAELVLVNFYADWCRFSQMLHPIFEEaaaKIKEEfpdAGKVVWGKVDCDKESDIADRYRINKYPTLKLFRNGM 89

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 392920290  38 SVFDIDSvEDFtEKVIQSSVPVIVDFHAEWCGPCQALGPRLEE-----KVNGRqgsVLLAKINV--DHAGELAMDYGISA 110
Cdd:cd02997    1 DVVHLTD-EDF-RKFLKKEKHVLVMFYAPWCGHCKKMKPEFTKaatelKEDGK---GVLAAVDCtkPEHDALKEEYNVKG 75

                         90
                 ....*....|.
gi 392920290 111 VPTVFAFKNGE 121
Cdd:cd02997   76 FPTFKYFENGK 86

TlpA-like family, DsbE (also known as CcmG and CycY) subfamily; DsbE is a membrane-anchored, periplasmic TRX-like reductase containing a CXXC motif that specifically donates reducing equivalents to apocytochrome c via CcmH, another cytochrome c maturation (Ccm) factor with a redox active CXXC motif. Assembly of cytochrome c requires the ligation of heme to reduced thiols of the apocytochrome. In bacteria, this assembly occurs in the periplasm. The reductase activity of DsbE in the oxidizing environment of the periplasm is crucial in the maturation of cytochrome c.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392920290  58 PVIVDFHAEWCGPCQALGPRLEEKvnGRQGSVLLAKIN-----------------------VDHAGELAMDYGISAVPTV 114
Cdd:cd03010   27 PYLLNVWASWCAPCREEHPVLMAL--ARQGRVPIYGINykdnpenalawlarhgnpyaavgFDPDGRVGIDLGVYGVPET 104

                         90       100
                 ....*....|....*....|...
gi 392920290 115 FAF-KNGEKISGFSGVLDDEQLD 136
Cdd:cd03010  105 FLIdGDGIIRYKHVGPLTPEVWE 127

Peroxiredoxin [Posttranslational modification, protein turnover, chaperones];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392920290  58 PVIVDFHAEWCGPCQALGPRLEEKVN--GRQGSVLLAkINV---------------------DHAGELAMDYGISAVPTV 114
Cdd:COG1225   23 PVVLYFYATWCPGCTAELPELRDLYEefKDKGVEVLG-VSSdsdeahkkfaekyglpfpllsDPDGEVAKAYGVRGTPTT 101

                         90       100       110
                 ....*....|....*....|....*....|....
gi 392920290 115 FAF-KNGeKI--SGFSGVLDDEQLDDFIEDVLAA 145
Cdd:COG1225  102 FLIdPDG-KIryVWVGPVDPRPHLEEVLEALLAE 134

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 392920290  60 IVDFHAEWCGPCQALGPRLEEKvnGRQGSVL---LAKINVDHAGELAMDYGISAVPTVFAFKNGEkISGFSGVLDDEQLD 136
Cdd:cd02994   20 MIEFYAPWCPACQQLQPEWEEF--ADWSDDLginVAKVDVTQEPGLSGRFFVTALPTIYHAKDGV-FRRYQGPRDKEDLI 96

                 ....*
gi 392920290 137 DFIED 141
Cdd:cd02994   97 SFIEE 101

Thioredoxin domain-containing protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392920290  50 EKVIQSSV-----PVIVDFHAEWCGPCQALGPRLEEKVNGRQGSVLLAKINVDHAGELAMDYGISAVPTVFAFKNGEKIS 124
Cdd:PTZ00443  41 EKLTQASTgattgPWFVKFYAPWCSHCRKMAPAWERLAKALKGQVNVADLDATRALNLAKRFAIKGYPTLLLFDKGKMYQ 120

                         90
                 ....*....|....
gi 392920290 125 GFSGVLDDEQLDDF 138
Cdd:PTZ00443 121 YEGGDRSTEKLAAF 134

Phosducin (Phd)-like family, Phd subfamily; Phd is a cytosolic regulator of G protein functions. It specifically binds G protein betagamma (Gbg)-subunits with high affinity, resulting in the solubilization of Gbg from the plasma membrane. This impedes the formation of a functional G protein trimer (G protein alphabetagamma), thereby inhibiting G protein-mediated signal transduction. Phd also inhibits the GTPase activity of G protein alpha. Phd can be phosphorylated by protein kinase A and G protein-coupled receptor kinase 2, leading to its inactivation. Phd was originally isolated from the retina, where it is highly expressed and has been implicated to play an important role in light adaptation. It is also found in the pineal gland, liver, spleen, striated muscle and the brain. The C-terminal domain of Phd adopts a thioredoxin fold, but it does not contain a CXXC motif. Phd interacts with G protein beta mostly through the N-terminal helical domain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392920290  25 SKMTQLRHFSHgasVFDIDSVEDFTEKV--IQSSVPVIVDFHAEWCGPCQALGPRLEeKVNGRQGSVLLAKInvdHAGEL 102
Cdd:cd02987   53 AKLPFGRRFGK---VYELDSGEQFLDAIdkEGKDTTVVVHIYEPGIPGCAALNSSLL-CLAAEYPAVKFCKI---RASAT 125

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 392920290 103 AMDYGIS--AVPTVFAFKNGEKISGFSGVLDDEqLDDFIEDVL 143
Cdd:cd02987  126 GASDEFDtdALPALLVYKGGELIGNFVRVTEDL-GEDFDAEDL 167

Phosducin (Phd)-like family; composed of Phd and Phd-like proteins (PhLP), characterized as cytosolic regulators of G protein functions. Phd and PhLPs specifically bind G protein betagamma (Gbg)-subunits with high affinity, resulting in the solubilization of Gbg from the plasma membrane and impeding G protein-mediated signal transduction by inhibiting the formation of a functional G protein trimer (G protein alphabetagamma). Phd also inhibits the GTPase activity of G protein alpha. Phd can be phosphorylated by protein kinase A and G protein-coupled receptor kinase 2, leading to its inactivation. Phd was originally isolated from the retina, where it is highly expressed and has been implicated to play an important role in light adaptation. It is also found in the pineal gland, liver, spleen, striated muscle and the brain. The C-terminal domain of Phd adopts a thioredoxin fold, but it does not contain a CXXC motif. Phd interacts with G protein beta mostly through the N-terminal helical domain. Also included in this family is a PhLP characterized as a viral inhibitor of apoptosis (IAP)-associated factor, named VIAF, that functions in caspase activation during apoptosis.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392920290  35 HGaSVFDIDSvEDFTEKVIQSS--VPVIVDFHAEWCGPCQALGPRLEEKVNgRQGSVLLAKINVDHAGeLAMDYGISAVP 112
Cdd:cd02957    3 FG-EVREISS-KEFLEEVTKASkgTRVVVHFYEPGFPRCKILDSHLEELAA-KYPETKFVKINAEKAF-LVNYLDIKVLP 78

                         90       100       110
                 ....*....|....*....|....*....|.
gi 392920290 113 TVFAFKNGEKISGFSGVLDDEQlDDFIEDVL 143
Cdd:cd02957   79 TLLVYKNGELIDNIVGFEELGG-DDFTTEDL 108

Glutaredoxin [Posttranslational modification, protein turnover, chaperones];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392920290  58 PVIVdFHAEWCGPCQALGPRLEEKvngrqgSVLLAKINVDH----AGELAMDYGISAVPTVFAfkNGEKISGFsgvlDDE 133
Cdd:COG0695    1 KVTL-YTTPGCPYCARAKRLLDEK------GIPYEEIDVDEdpeaREELRERSGRRTVPVIFI--GGEHLGGF----DEG 67

                 ....*..
gi 392920290 134 QLDDFIE 140
Cdd:COG0695   68 ELDALLA 74

Thioredoxin-like domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392920290   58 PVIVDFHAEWCGPCQALGPRLEEKVNGR---QGSVLLAKINVDHAG-------------ELAMDYGISAVPTVFAFKNGE 121
Cdd:pfam13098   6 PVLVVFTDPDCPYCKKLKKELLEDPDVTvylGPNFVFIAVNIWCAKevakaftdilenkELGRKYGVRGTPTIVFFDGKG 85

                          90
                  ....*....|....*...
gi 392920290  122 KISGFSGVLDDEQLDDFI 139
Cdd:pfam13098  86 ELLRLPGYVPAEEFLALL 103

thiol-disulfide oxidoreductase ResA;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392920290  59 VIVDFHAEWCGPCQALGPRLEE--KVNGRQGSVLLAkINVDHAgELAMD-----------------------YGISAVPT 113
Cdd:PRK03147  64 VFLNFWGTWCKPCEKEMPYMNElyPKYKEKGVEIIA-VNVDET-ELAVKnfvnrygltfpvaidkgrqvidaYGVGPLPT 141

                         90       100       110
                 ....*....|....*....|....*....|
gi 392920290 114 VFAF-KNGEKISGFSGVLDDEQLDDFIEDV 142
Cdd:PRK03147 142 TFLIdKDGKVVKVITGEMTEEQLEEYLEKI 171

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 392920290  45 VEDFTEKVIQSSVPVI--VDFHAEWCGPCQALGPRLEE---KVNGRQGSVLLAKINVDHAGELAMDYGISAVPTVFAFKN 119
Cdd:cd03000    2 VLDLDDSFKDVRKEDIwlVDFYAPWCGHCKKLEPVWNEvgaELKSSGSPVRVGKLDATAYSSIASEFGVRGYPTIKLLKG 81

                 .
gi 392920290 120 G 120
Cdd:cd03000   82 D 82

PDIa family, N-terminal ERdj5 subfamily; ERdj5, also known as JPDI and macrothioredoxin, is a protein containing an N-terminal DnaJ domain and four redox active TRX domains. This subfamily is comprised of the first TRX domain of ERdj5 located after the DnaJ domain at the N-terminal half of the protein. ERdj5 is a ubiquitous protein localized in the endoplasmic reticulum (ER) and is abundant in secretory cells. It's transcription is induced during ER stress. It interacts with BiP through its DnaJ domain in an ATP-dependent manner. BiP, an ER-resident member of the Hsp70 chaperone family, functions in ER-associated degradation and protein translocation.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 392920290  60 IVDFHAEWCGPCQALGPRLEEKVNGRQGSVLLAKINVDHAGELAMDYGISAVPTVFAFKNGEKISGFSGVLDDEQLDDF 138
Cdd:cd03003   22 FVNFYSPRCSHCHDLAPTWREFAKEMDGVIRIGAVNCGDDRMLCRSQGVNSYPSLYVFPSGMNPEKYYGDRSKESLVKF 100

TRX family, chloroplastic drought-induced stress protein of 32 kD (CDSP32); CDSP32 is composed of two TRX domains, a C-terminal TRX domain which contains a redox active CXXC motif and an N-terminal TRX-like domain which contains an SXXS sequence instead of the redox active motif. CDSP32 is a stress-inducible TRX, i.e., it acts as a TRX by reducing protein disulfides and is induced by environmental and oxidative stress conditions. It plays a critical role in plastid defense against oxidative damage, a role related to its function as a physiological electron donor to BAS1, a plastidic 2-cys peroxiredoxin. Plants lacking CDSP32 exhibit decreased photosystem II photochemical efficiencies and chlorophyll retention compared to WT controls, as well as an increased proportion of BAS1 in its overoxidized monomeric form.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392920290  59 VIVDFHAEWCGPCQALGPRLEeKVNGRQGSVLLAKINVDHAG---ELAMDYGISAVPTVFAFKNGEKISGFSGVLDDEQL 135
Cdd:cd02985   18 VVLEFALKHSGPSVKIYPTMV-KLSRTCNDVVFLLVNGDENDstmELCRREKIIEVPHFLFYKDGEKIHEEEGIGPDELI 96

                 ..
gi 392920290 136 DD 137
Cdd:cd02985   97 GD 98

Endoplasmic reticulum protein 19 (ERp19) family; ERp19 is also known as ERp18, a protein located in the ER containing one redox active TRX domain. Denaturation studies indicate that the reduced form is more stable than the oxidized form, suggesting that the protein is involved in disulfide bond formation. In vitro, ERp19 has been shown to possess thiol-disulfide oxidase activity which is dependent on the presence of both active site cysteines. Although described as protein disulfide isomerase (PDI)-like, the protein does not complement for PDI activity. ERp19 shows a wide tissue distribution but is most abundant in liver, testis, heart and kidney.

                         10        20        30
                 ....*....|....*....|....*....|....*..
gi 392920290  44 SVEDFTEKVIQSSVPVIVDFHAEWCGPCQALGPRLEE 80
Cdd:cd02959    7 TLEDGIKEAKDSGKPLMLLIHKTWCGACKALKPKFAE 43