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 24639826  13 QQLILAEDKLVVIDFYADWCGPCKIIAPKLDELAQQYSDRVVVLKVNVDENEDITVEYNVNSMPTFVFIKGGNVLELFVG 92
Cdd:COG3118  11 EEEVLESDKPVLVDFWAPWCGPCKMLAPVLEELAAEYGGKVKFVKVDVDENPELAAQFGVRSIPTLLLFKDGQPVDRFVG 90

                        90
                ....*....|....
gi 24639826  93 -CNSDKLAKLMEKH 105
Cdd:COG3118  91 aLPKEQLREFLDKV 104

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 24639826   9 DDLDQqlILAEDKLVVIDFYADWCGPCKIIAPKLDELAQQYsDRVVVLKVNVDENEDITVEYNVNSMPTFVFIKGGNVLE 88
Cdd:cd02947   1 EEFEE--LIKSAKPVVVDFWAPWCGPCKAIAPVLEELAEEY-PKVKFVKVDVDENPELAEEYGVRSIPTFLFFKNGKEVD 77

                        90
                ....*....|....*.
gi 24639826  89 LFVGCNS-DKLAKLME 103
Cdd:cd02947  78 RVVGADPkEELEEFLE 93

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 24639826  13 QQLILAEDKLVVIDFYADWCGPCKIIAPKLDELAQQYSDRVVVLKVNVDENEDITVEYNVNSMPTFVFIKGGNVLELFVG 92
Cdd:COG3118  11 EEEVLESDKPVLVDFWAPWCGPCKMLAPVLEELAAEYGGKVKFVKVDVDENPELAAQFGVRSIPTLLLFKDGQPVDRFVG 90

                        90
                ....*....|....
gi 24639826  93 -CNSDKLAKLMEKH 105
Cdd:COG3118  91 aLPKEQLREFLDKV 104

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 24639826   9 DDLDQqlILAEDKLVVIDFYADWCGPCKIIAPKLDELAQQYsDRVVVLKVNVDENEDITVEYNVNSMPTFVFIKGGNVLE 88
Cdd:cd02947   1 EEFEE--LIKSAKPVVVDFWAPWCGPCKAIAPVLEELAEEY-PKVKFVKVDVDENPELAEEYGVRSIPTFLFFKNGKEVD 77

                        90
                ....*....|....*.
gi 24639826  89 LFVGCNS-DKLAKLME 103
Cdd:cd02947  78 RVVGADPkEELEEFLE 93

thioredoxin TrxA;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24639826    9 DDLDQQLILAEDKLVVIDFYADWCGPCKIIAPKLDELAQQYSDRVVVLKVNVDENEDITVEYNVNSMPTFVFIKGGNVLE 88
Cdd:PRK09381  10 DDSFDTDVLKADGAILVDFWAEWCGPCKMIAPILDEIADEYQGKLTVAKLNIDQNPGTAPKYGIRGIPTLLLFKNGEVAA 89

                 ....*..
gi 24639826   89 LFVGCNS 95
Cdd:PRK09381  90 TKVGALS 96

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 24639826   7 NKDDLDQqlILAEDKLVVIDFYADWCGPCKIIAPKLDELAQQY--SDRVVVLKVNVDENEDITVEYNVNSMPTFVFIKGG 84
Cdd:cd02961   4 TDDNFDE--LVKDSKDVLVEFYAPWCGHCKALAPEYEKLAKELkgDGKVVVAKVDCTANNDLCSEYGVRGYPTIKLFPNG 81

                .
gi 24639826  85 N 85
Cdd:cd02961  82 S 82

TRX-like protein A (TxlA) family; TxlA was originally isolated from the cyanobacterium Synechococcus. It is found only in oxygenic photosynthetic organisms. TRX is a small enzyme that participate in redox reactions, via the reversible oxidation of an active site dithiol present in a CXXC motif. Disruption of the txlA gene suggests that the protein is involved in the redox regulation of the structure and function of photosynthetic apparatus. The plant homolog (designated as HCF164) is localized in the chloroplast and is involved in the assembly of the cytochrome b6f complex, which takes a central position in photosynthetic electron transport.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 24639826  17 LAEDKLVVIDFYADWCGPCKIIAPKLDELAQQYSDRVVVLKVNVDEN--EDITVEYNVNSMPTFVFI-KGGNVLELFVG 92
Cdd:cd02950  17 LSNGKPTLVEFYADWCTVCQEMAPDVAKLKQKYGDQVNFVMLNVDNPkwLPEIDRYRVDGIPHFVFLdREGNEEGQSIG 95

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 24639826  14 QLILAEDKLVVIDFYADWCGPCKIIAPKLDELAQQYSDR--VVVLKVNVDENeDITVEYNVNSMPTFVFIKGGN 85
Cdd:cd02995  12 EVVLDSDKDVLVEFYAPWCGHCKALAPIYEELAEKLKGDdnVVIAKMDATAN-DVPSEFVVDGFPTILFFPAGD 84

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 24639826    14 QLILAEDKLVVIDFYADWCGPCKIIAPKLDELAQQYSDR---VVVLKVNVDENEdiTVEYNVNSMPTFVFIKGGNVLELF 90
Cdd:TIGR01130 358 EIVLDETKDVLVEFYAPWCGHCKNLAPIYEELAEKYKDAesdVVIAKMDATAND--VPPFEVEGFPTIKFVPAGKKSEPV 435

                          90       100
                  ....*....|....*....|....*..
gi 24639826    91 V---GCNSDKLAKLMEKHAGVYTDEAA 114
Cdd:TIGR01130 436 PydgDRTLEDFSKFIAKHATFPLEGKA 462

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 24639826  13 QQLILAEDKLVVIDFYADWCGPCKIIAPKLDELAQQYS--DRVVVLKVNVDE-NEDITVEYNVNSMPTFVFIKGGN 85
Cdd:cd02998  11 DKVVGDDKKDVLVEFYAPWCGHCKNLAPEYEKLAAVFAneDDVVIAKVDADEaNKDLAKKYGVSGFPTLKFFPKGS 86

TRX domain, TRX and NDP-kinase (NDPK) fusion protein family; most members of this group are fusion proteins which contain one redox active TRX domain containing a CXXC motif and three NDPK domains, and are characterized as intermediate chains (ICs) of axonemal outer arm dynein. Dyneins are molecular motors that generate force against microtubules to produce cellular movement, and are divided into two classes: axonemal and cytoplasmic. They are supramolecular complexes consisting of three protein groups classified according to size: dynein heavy, intermediate and light chains. Axonemal dyneins form two structures, the inner and outer arms, which are attached to doublet microtubules throughout the cilia and flagella. The human homolog is the sperm-specific Sptrx-2, presumed to be a component of the human sperm axoneme architecture. Included in this group is another human protein, TRX-like protein 2, a smaller fusion protein containing one TRX and one NDPK domain, which is also associated with microtubular structures. The other members of this group are hypothetical insect proteins containing a TRX domain and outer arm dynein light chains (14 and 16kDa) of Chlamydomonas reinhardtii. Using standard assays, the fusion proteins have shown no TRX enzymatic activity.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24639826  17 LAEDKLVVIDFYADWCGPCKIIAPKLDELAQQYSDRVVVLKVNVDENEDITVEYNVNSMPTFVFIKGGNVLELFVGCNSD 96
Cdd:cd02948  14 LSNKGLTVVDVYQEWCGPCKAVVSLFKKIKNELGDDLLHFATAEADTIDTLKRYRGKCEPTFLFYKNGELVAVIRGANAP 93

                ....*....
gi 24639826  97 KLAKLMEKH 105
Cdd:cd02948  94 LLNKTITEL 102

Thioredoxin-related protein SoxW [Posttranslational modification, protein turnover, chaperones];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24639826   8 KDDLDQQLILA--EDKLVVIDFYADWCGPCKiiapKLD-------ELAQQYSDRVVVLKVNVDENEDIT----------- 67
Cdd:COG2143  26 LLDLEEDLALAkaEGKPILLFFESDWCPYCK----KLHkevfsdpEVAAYLKENFVVVQLDAEGDKEVTdfdgetlteke 101

                        90       100
                ....*....|....*....|....*...
gi 24639826  68 --VEYNVNSMPTFVFI-KGGNVLELFVG 92
Cdd:COG2143 102 laRKYGVRGTPTLVFFdAEGKEIARIPG 129

PDIa family, C-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 composed of the three TRX domains located at the C-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. Also included in the alignment is the single complete TRX domain of an uncharacterized protein from Tetraodon nigroviridis, which also contains a DnaJ domain at its N-terminus.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 24639826  24 VIDFYADWCGPCKIIAPKLDELAQQYSDRVVVLKVNVDENEDITVEYNVNSMPTFVFIKGG 84
Cdd:cd03004  23 LVDFYAPWCGPCQALLPELRKAARALKGKVKVGSVDCQKYESLCQQANIRAYPTIRLYPGN 83

Peroxiredoxin [Posttranslational modification, protein turnover, chaperones];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24639826  20 DKLVVIDFYADWCGPCKIIAPKLDELAQQYSDR-VVVLKVNV---------------------DENEDITVEYNVNSMPT 77
Cdd:COG1225  21 GKPVVLYFYATWCPGCTAELPELRDLYEEFKDKgVEVLGVSSdsdeahkkfaekyglpfpllsDPDGEVAKAYGVRGTPT 100

                        90
                ....*....|....*.
gi 24639826  78 FVFI-KGGNVLELFVG 92
Cdd:COG1225 101 TFLIdPDGKIRYVWVG 116

disulphide isomerase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24639826   14 QLILAEDKLVVIDFYADWCGPCKIIAPKLDELAQQY--SDRVVVLKVNVDENEDITVEYNVNSMPTFVFIKGGNVLEL-F 90
Cdd:PTZ00102 369 EIVFKSDKDVLLEIYAPWCGHCKNLEPVYNELGEKYkdNDSIIVAKMNGTANETPLEEFSWSAFPTILFVKAGERTPIpY 448

                         90
                 ....*....|....*....
gi 24639826   91 VGCNSDK-LAKLMEKHAGV 108
Cdd:PTZ00102 449 EGERTVEgFKEFVNKHATN 467

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 24639826  16 ILAEDKLVVIDFYADWCGPCKIIAPKLDELAQQY------SDRVVVLKVNVDENEDITVEYNVNSMPTF-VFIKG 83
Cdd:cd02996  14 ILQSAELVLVNFYADWCRFSQMLHPIFEEAAAKIkeefpdAGKVVWGKVDCDKESDIADRYRINKYPTLkLFRNG 88

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 24639826  24 VIDFYADWCGPCKIIAPKLDELAqQYSDRVVVLKVNVDENEDITVE---YNVNSMPTFVFIKGGNVLELF 90
Cdd:cd01659   1 LVLFYAPWCPFCQALRPVLAELA-LLNKGVKFEAVDVDEDPALEKElkrYGVGGVPTLVVFGPGIGVKYG 69

TRX domain, novel NADPH thioredoxin reductase (NTR) family; composed of fusion proteins found only in oxygenic photosynthetic organisms containing both TRX and NTR domains. The TRX domain functions as a protein disulfide reductase via the reversible oxidation of an active center dithiol present in a CXXC motif, while the NTR domain functions as a reductant to oxidized TRX. The fusion protein is bifunctional, showing both TRX and NTR activities, but it is not an independent NTR/TRX system. In plants, the protein is found exclusively in shoots and mature leaves and is localized in the chloroplast. It is involved in plant protection against oxidative stress.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 24639826  20 DKLVVIDFYADWCGPCKIIAPKLDELAQQYSDRVVVLKVNVDENEDITVEYNVNSMPTFVFIK 82
Cdd:cd02949  13 DRLILVLYTSPTCGPCRTLKPILNKVIDEFDGAVHFVEIDIDEDQEIAEAAGIMGTPTVQFFK 75

Thioredoxin-like; Thioredoxins are small enzymes that participate in redox reactions, via the reversible oxidation of an active centre disulfide bond.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24639826    20 DKLVVIDFYADWCGPCKIIAPKLDELAQQYS--DRVVVLKVNVDENED-------------------------ITVEYNV 72
Cdd:pfam13905   1 GKVVLLYFGASWCKPCRRFTPLLKELYEKLKkkKNVEIVFVSLDRDLEefkdylkkmpkdwlsvpfddderneLKRKYGV 80

                          90
                  ....*....|....*
gi 24639826    73 NSMPTFVFI-KGGNV 86
Cdd:pfam13905  81 NAIPTLVLLdPNGEV 95

thiol-disulfide oxidoreductase ResA;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24639826   10 DLDQQLILAED---KLVVIDFYADWCGPCKIIAPKLDELAQQYSDRVV-VLKVNVDENEdITVE---------------- 69
Cdd:PRK03147  48 DLEGKKIELKDlkgKGVFLNFWGTWCKPCEKEMPYMNELYPKYKEKGVeIIAVNVDETE-LAVKnfvnrygltfpvaidk 126

                         90       100       110
                 ....*....|....*....|....*....|.
gi 24639826   70 -------YNVNSMPTFVFI-KGGNVLELFVG 92
Cdd:PRK03147 127 grqvidaYGVGPLPTTFLIdKDGKVVKVITG 157

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 24639826   5 VRNKDDLDQQLILAEDKLvvIDFYADWCGPCKIIAPKLDELAQQYSD-RVVVLKVNVDENEDITVEYNVNSMPTFVFIKG 83
Cdd:cd02994   3 VVELTDSNWTLVLEGEWM--IEFYAPWCPACQQLQPEWEEFADWSDDlGINVAKVDVTQEPGLSGRFFVTALPTIYHAKD 80

                .
gi 24639826  84 G 84
Cdd:cd02994  81 G 81

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 24639826   2 VYPVRNKDDLDQQLILAEDKLVVIDFYADWCGPCKIIAPKLDELAQQYSDrVVVLKVNVdENEDITVEYNVNSMPTFVFI 81
Cdd:cd02957   6 VREISSKEFLEEVTKASKGTRVVVHFYEPGFPRCKILDSHLEELAAKYPE-TKFVKINA-EKAFLVNYLDIKVLPTLLVY 83

                        90
                ....*....|.
gi 24639826  82 KGGNVLELFVG 92
Cdd:cd02957  84 KNGELIDNIVG 94

PDIa family, Quiescin-sulfhydryl oxidase (QSOX) subfamily; QSOX is a eukaryotic protein containing an N-terminal redox active TRX domain, similar to that of PDI, and a small C-terminal flavin adenine dinucleotide (FAD)-binding domain homologous to the yeast ERV1p protein. QSOX oxidizes thiol groups to disulfides like PDI, however, unlike PDI, this oxidation is accompanied by the reduction of oxygen to hydrogen peroxide. QSOX is localized in high concentrations in cells with heavy secretory load and prefers peptides and proteins as substrates, not monothiols like glutathione. Inside the cell, QSOX is found in the endoplasmic reticulum and Golgi. The flow of reducing equivalents in a QSOX-catalyzed reaction goes from the dithiol substrate -> dithiol of the QSOX TRX domain -> dithiols of the QSOX ERV1p domain -> FAD -> oxygen.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 24639826  24 VIDFYADWCGPCKIIAPKLDELAQQYSDRVVVLKVNV-----DENEDITVEYNVNSMPTFVFIK 82
Cdd:cd02992  23 LVEFYASWCGHCRAFAPTWKKLARDLRKWRPVVRVAAvdcadEENVALCRDFGVTGYPTLRYFP 86

AhpC/TSA family; This family contains proteins related to alkyl hydroperoxide reductase (AhpC) and thiol specific antioxidant (TSA).

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 24639826    19 EDKLVVIDFYA-DWCGPCKIIAPKLDELAQQYSDR-VVVLKVNVD 61
Cdd:pfam00578  24 RGKWVVLFFYPaDWTPVCTTELPALADLYEEFKKLgVEVLGVSVD 68

PDIa family, 5'-Adenylylsulfate (APS) reductase subfamily; composed of plant-type APS reductases containing a C-terminal redox active TRX domain and an N-terminal reductase domain which is part of a superfamily that includes N type ATP PPases. APS reductase catalyzes the reduction of activated sulfate to sulfite, a key step in the biosynthesis of sulfur-containing metabolites. Sulfate is first activated by ATP sulfurylase, forming APS, which can be phosphorylated to 3'-phosphoadenosine-5'-phosphosulfate (PAPS). Depending on the organism, either APS or PAPS can be used for sulfate reduction. Prokaryotes and fungi use PAPS, whereas plants use both APS and PAPS. Since plant-type APS reductase uses glutathione (GSH) as its electron donor, the C-terminal domain may function like glutaredoxin, a GSH-dependent member of the TRX superfamily. The flow of reducing equivalents goes from GSH -> C-terminal TRX domain -> N-terminal reductase domain -> APS. Plant-type APS reductase shows no homology to that of dissimilatory sulfate-reducing bacteria, which is an iron-sulfur flavoenzyme. Also included in the alignment is EYE2 from Chlamydomonas reinhardtii, a protein required for eyespot assembly.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24639826  18 AEDKLVVIdfYADWCGPCKIIAPKLDELAQQYSDR-VVVLKVNVDENEDITVEYN--VNSMPTFVFIKGG 84
Cdd:cd02993  21 NQSTLVVL--YAPWCPFCQAMEASYEELAEKLAGSnVKVAKFNADGEQREFAKEElqLKSFPTILFFPKN 88

Thioredoxin;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24639826     9 DDLDQQLILAEDKLVVIDFYADWCGPCKIIAPKLDELAQQYSDrvvvLKVNV---DENEDITVEYNVN---SMPTFVFI- 81
Cdd:pfam14595  30 EELIEKIKSIEKPLRILVITEDWCGDAAQNVPVLAKIAELNPN----IELRIllrDENLELMDQYLTGggrAIPTFIFLd 105

                          90
                  ....*....|
gi 24639826    82 KGGNVLELFV 91
Cdd:pfam14595 106 EDGEELGVWG 115

Dim1 family; Dim1 is also referred to as U5 small nuclear ribonucleoprotein particle (snRNP)-specific 15kD protein. It is a component of U5 snRNP, which pre-assembles with U4/U6 snRNPs to form a [U4/U6:U5] tri-snRNP complex required for pre-mRNA splicing. Dim1 interacts with multiple splicing-associated proteins, suggesting that it functions at multiple control points in the splicing of pre-mRNA as part of a large spliceosomal complex involving many protein-protein interactions. U5 snRNP contains seven core proteins (common to all snRNPs) and nine U5-specific proteins, one of which is Dim1. Dim1 adopts a thioredoxin fold but does not contain the redox active CXXC motif. It is essential for G2/M phase transition, as a consequence to its role in pre-mRNA splicing.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 24639826   7 NKDDLDQQLILAEDKLVVIDFYADWCGPCKIIAPKLDELAQQYSDRVVVLKVNVDENEDITVEYNVNSMPTFVF 80
Cdd:cd02954   1 SGWAVDQAILSEEEKVVVIRFGRDWDPVCMQMDEVLAKIAEDVSNFAVIYLVDIDEVPDFNKMYELYDPPTVMF 74

PDIa family, N-terminal EFP1 subfamily; EFP1 is a binding partner protein of thyroid oxidase (ThOX), also called Duox. ThOX proteins are responsible for the generation of hydrogen peroxide, a crucial substrate of thyroperoxidase, which functions to iodinate thyroglobulin and synthesize thyroid hormones. EFP1 was isolated through a yeast two-hybrid method using the EF-hand fragment of dog Duox1 as a bait. It could be one of the partners in the assembly of a multiprotein complex constituting the thyroid hydrogen peroxide generating system. EFP1 contains two TRX domains related to the redox active TRX domains of protein disulfide isomerase (PDI). This subfamily is composed of the N-terminal TRX domain of EFP1, which contains a CXXS sequence in place of the typical CXXC motif, similar to ERp44. The CXXS motif allows the formation of stable mixed disulfides, crucial for the ER-retention function of ERp44.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 24639826   8 KDDLDQQLILAED-KLVVIDFYADWCGPCKIIAPKLDELAQQYSDRVVVLKVN 59
Cdd:cd03006  16 KGQLDYAEELRTDaEVSLVMYYAPWDAQSQAARQEFEQVAQKLSDQVLFVAIN 68

periplasmic protein thiol:disulfide oxidoreductases, DsbE subfamily; Involved in the biogenesis of c-type cytochromes as well as in disulfide bond formation in some periplasmic proteins. [Protein fate, Protein folding and stabilization]

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 24639826     6 RNKDDLDQQLILAEDKLVVIDFYADWCGPCKIIAPKLDELAQqysDRVVVLKVNVDENED 65
Cdd:TIGR00385  49 DEPGQFYTADVLTQGKPVLLNVWASWCPPCRAEHPYLNELAK---QGLPIVGVDYKDDRQ 105