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 578837158  72 DRVVNSETPVVVDFHAQWCGPCKILGPRLEKmVAKQHGKVVMAKVDIDDHTDLAIEYEVSAVPTVLAMKNGDVVDKFVGI 151
Cdd:cd02947    4 EELIKSAKPVVVDFWAPWCGPCKAIAPVLEE-LAEEYPKVKFVKVDVDENPELAEEYGVRSIPTFLFFKNGKEVDRVVGA 82

                         90
                 ....*....|.
gi 578837158 152 KDEDQLEAFLK 162
Cdd:cd02947   83 DPKEELEEFLE 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 578837158   70 FQDRVVNSETPVVVDFHAQWCGPCKILGPRLEKMVAKQHGKVVMAKVDIDDHTDLAIEYEVSAVPTVLAMKNGDVVDKFV 149
Cdd:pfam00085  10 FDEVVQKSSKPVLVDFYAPWCGPCKMLAPEYEELAQEYKGNVVFAKVDVDENPDLASKYGVRGYPTLIFFKNGQPVDDYV 89

                          90
                  ....*....|....
gi 578837158  150 GIKDEDQLEAFLKK 163
Cdd:pfam00085  90 GARPKDALAAFLKA 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 578837158  72 DRVVNSETPVVVDFHAQWCGPCKILGPRLEKmVAKQHGKVVMAKVDIDDHTDLAIEYEVSAVPTVLAMKNGDVVDKFVGI 151
Cdd:cd02947    4 EELIKSAKPVVVDFWAPWCGPCKAIAPVLEE-LAEEYPKVKFVKVDVDENPELAEEYGVRSIPTFLFFKNGKEVDRVVGA 82

                         90
                 ....*....|.
gi 578837158 152 KDEDQLEAFLK 162
Cdd:cd02947   83 DPKEELEEFLE 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 578837158   70 FQDRVVNSETPVVVDFHAQWCGPCKILGPRLEKMVAKQHGKVVMAKVDIDDHTDLAIEYEVSAVPTVLAMKNGDVVDKFV 149
Cdd:pfam00085  10 FDEVVQKSSKPVLVDFYAPWCGPCKMLAPEYEELAQEYKGNVVFAKVDVDENPDLASKYGVRGYPTLIFFKNGQPVDDYV 89

                          90
                  ....*....|....
gi 578837158  150 GIKDEDQLEAFLKK 163
Cdd:pfam00085  90 GARPKDALAAFLKA 103

thioredoxin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578837158  72 DRVVNSETPVVVDFHAQWCGPCKILGPRLEKMvAKQHGKVVMAKVDIDDHTDLAIEYEVSAVPTVLAMKNGDVVDKFVGI 151
Cdd:PTZ00051  12 ESTLSQNELVIVDFYAEWCGPCKRIAPFYEEC-SKEYTKMVFVKVDVDELSEVAEKENITSMPTFKVFKNGSVVDTLLGA 90

                 ...
gi 578837158 152 KDE 154
Cdd:PTZ00051  91 NDE 93

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578837158  68 PDFQDRVVNSET----PVVVDFHAQWCGPCKILGPRLEKmVAKQHGKVVMAKVDIDDHTD-------------------- 123
Cdd:COG0526   14 TDLDGKPLSLADlkgkPVLVNFWATWCPPCRAEMPVLKE-LAEEYGGVVFVGVDVDENPEavkaflkelglpypvlldpd 92

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 578837158 124 --LAIEYEVSAVP-TVLAMKNGDVVDKFVGIKDEDQLEAFLKKLIG 166
Cdd:COG0526   93 geLAKAYGVRGIPtTVLIDKDGKIVARHVGPLSPEELEEALEKLLA 138

thioredoxin 2; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578837158  72 DRVVNSETPVVVDFHAQWCGPCKILGPRLEKMVAKQHGKVVMAKVDIDDHTDLAIEYEVSAVPTVLAMKNGDVVDKFVGI 151
Cdd:PRK10996  46 DKLLQDDLPVVIDFWAPWCGPCRNFAPIFEDVAAERSGKVRFVKVNTEAERELSARFRIRSIPTIMIFKNGQVVDMLNGA 125

                         90
                 ....*....|
gi 578837158 152 KDEDQLEAFL 161
Cdd:PRK10996 126 VPKAPFDSWL 135

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 578837158   69 DFQDRVVNSETpVVVDFHAQWCGPCKILGPRLEK---MVAKQHGKVVMAKVDIDDHTDLAIEYEVSAVPTVLAMKNGDVV 145
Cdd:TIGR01130  10 NFDDFIKSHEF-VLVEFYAPWCGHCKSLAPEYEKaadELKKKGPPIKLAKVDATEEKDLAQKYGVSGYPTLKIFRNGEDS 88

                          90       100
                  ....*....|....*....|..
gi 578837158  146 DK-FVGIKDEDQLEAFLKKLIG 166
Cdd:TIGR01130  89 VSdYNGPRDADGIVKYMKKQSG 110

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 578837158  69 DFQDRVVNSETPVVVDFHAQWCGPCKILGPRLEKMVAKQHGKVVMAKVDIDDHTDLAIEYEVSAVPTV 136
Cdd:cd03004   10 DFPELVLNRKEPWLVDFYAPWCGPCQALLPELRKAARALKGKVKVGSVDCQKYESLCQQANIRAYPTI 77

disulphide isomerase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578837158  81 VVVDFHAQWCGPCKILGPRLEK---MVAKQHGKVVMAKVDIDDHTDLAIEYEVSAVPTVLAMKNGDVVdKFVGIKDEDQL 157
Cdd:PTZ00102  52 VLVKFYAPWCGHCKRLAPEYKKaakMLKEKKSEIVLASVDATEEMELAQEFGVRGYPTIKFFNKGNPV-NYSGGRTADGI 130

                 ....*....
gi 578837158 158 EAFLKKLIG 166
Cdd:PTZ00102 131 VSWIKKLTG 139

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 578837158  57 ISLTTFNIQDgpdfqdrVVNSETPVVVDFHAQWCGPCKILGPRLEKMVAK------QHGKVVMAKVDIDDHTDLAIEYEV 130
Cdd:cd02996    4 VSLTSGNIDD-------ILQSAELVLVNFYADWCRFSQMLHPIFEEAAAKikeefpDAGKVVWGKVDCDKESDIADRYRI 76

                         90
                 ....*....|....*..
gi 578837158 131 SAVPTVLAMKNGDVVDK 147
Cdd:cd02996   77 NKYPTLKLFRNGMMMKR 93

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 578837158  72 DRVV-NSETPVVVDFHAQWCGPCKILGPRLEKMVAKQHGKVVMAKVDIDD--HTDLAIEYEVSAVPTV 136
Cdd:cd03002   11 DKVVhNTNYTTLVEFYAPWCGHCKNLKPEYAKAAKELDGLVQVAAVDCDEdkNKPLCGKYGVQGFPTL 78

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 578837158  66 DGPDFQDRVVNS--ETPVVVDFHAQWCGPCKILGPRLEKMvAKQHGKVVMAKVDIDDhTDLAIEYEVSAVPTVLAMKNGD 143
Cdd:cd02957   10 SSKEFLEEVTKAskGTRVVVHFYEPGFPRCKILDSHLEEL-AAKYPETKFVKINAEK-AFLVNYLDIKVLPTLLVYKNGE 87

                         90       100
                 ....*....|....*....|....*.
gi 578837158 144 VVDKFVGIKD-------EDQLEAFLK 162
Cdd:cd02957   88 LIDNIVGFEElggddftTEDLEKFLA 113

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        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578837158  77 SETPVVVDFHAQWCGPCKILGPRLEKMVAKQHGKVVMAKVDIDDHTDLAIEYEVSAVPTVLAMKNGDVVDKFVGIKDEDQ 156
Cdd:cd02949   12 SDRLILVLYTSPTCGPCRTLKPILNKVIDEFDGAVHFVEIDIDEDQEIAEAAGIMGTPTVQFFKDKELVKEISGVKMKSE 91

                 ....*.
gi 578837158 157 LEAFLK 162
Cdd:cd02949   92 YREFIE 97

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578837158  80 PVVVDFHAQWCGPCKILGPRLEKMVAKQHGKV--VMAKVDIDDHTDLAIEYEVSAVPT-VLAMKNGDVVDKFVGIKDEDQ 156
Cdd:cd02950   22 PTLVEFYADWCTVCQEMAPDVAKLKQKYGDQVnfVMLNVDNPKWLPEIDRYRVDGIPHfVFLDREGNEEGQSIGLQPKQV 101

                 ....*....
gi 578837158 157 LEAFLKKLI 165
Cdd:cd02950  102 LAQNLDALV 110

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 578837158  82 VVDFHAQWCGPCKILGPRLEKMVAKQHGkVVMAKVDIDDHTDL---AIEYEVSAVPTVLAMKNGDVV 145
Cdd:cd01659    1 LVLFYAPWCPFCQALRPVLAELALLNKG-VKFEAVDVDEDPALekeLKRYGVGGVPTLVVFGPGIGV 66

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 578837158  83 VDFHAQWCGPCKILGPRLEKMVA--KQHGKVV-MAKVDIDDHTDLAIEYEVSAVPTVLAMKnGDVVDKFVGIKDEDQLEA 159
Cdd:cd03000   20 VDFYAPWCGHCKKLEPVWNEVGAelKSSGSPVrVGKLDATAYSSIASEFGVRGYPTIKLLK-GDLAYNYRGPRTKDDIVE 98

                 ....*
gi 578837158 160 FLKKL 164
Cdd:cd03000   99 FANRV 103

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 578837158  83 VDFHAQWCGPCKILGPRLEKMVAK-QHGKVVMAKVDIDDHTDLAIEYEVSAVPTVLAMKNGdVVDKFVGIKDEDQLEAFL 161
Cdd:cd02994   21 IEFYAPWCPACQQLQPEWEEFADWsDDLGINVAKVDVTQEPGLSGRFFVTALPTIYHAKDG-VFRRYQGPRDKEDLISFI 99

                 ..
gi 578837158 162 KK 163
Cdd:cd02994  100 EE 101

DsbD gamma family; DsbD gamma is the C-terminal periplasmic domain of the bacterial protein DsbD. It contains a CXXC motif in a TRX fold and shuttles the reducing potential from the membrane domain (DsbD beta) to the N-terminal periplasmic domain (DsbD alpha). DsbD beta, a transmembrane domain comprising of eight helices, acquires its reducing potential from the cytoplasmic thioredoxin. DsbD alpha transfers the acquired reducing potential from DsbD gamma to target proteins such as the periplasmic protein disulphide isomerases, DsbC and DsbG. This flow of reducing potential from the cytoplasm through DsbD allows DsbC and DsbG to act as isomerases in the oxidizing environment of the bacterial periplasm. DsbD also transfers reducing potential from the cytoplasm to specific reductases in the periplasm which are involved in the maturation of cytochromes.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 578837158  80 PVVVDFHAQWCGPCKIlgprLEKMV-------AKQHGKVVMAKVDI----DDHTDLAIEYEVSAVPTVL 137
Cdd:cd02953   13 PVFVDFTADWCVTCKV----NEKVVfsdpevqAALKKDVVLLRADWtkndPEITALLKRFGVFGPPTYL 77

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        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 578837158  66 DGPDFQDRVVNSETPVVVDFHAQWCGPCKILGP---RLEKMVAKQHGKVVMAKVD--IDDHTDLAIEYEVSAVPTV 136
Cdd:cd02992    7 DAASFNSALLGSPSAWLVEFYASWCGHCRAFAPtwkKLARDLRKWRPVVRVAAVDcaDEENVALCRDFGVTGYPTL 82

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 578837158  62 FNIQDGPDFQDRV--VNSETPVVVDFHAQWCGPCKILGPRLEKMvAKQHGKVVMAKVdIDDHTDLAIEYEVSAVPTVLAM 139
Cdd:cd02987   65 YELDSGEQFLDAIdkEGKDTTVVVHIYEPGIPGCAALNSSLLCL-AAEYPAVKFCKI-RASATGASDEFDTDALPALLVY 142

                         90       100       110
                 ....*....|....*....|....*....|.
gi 578837158 140 KNGDVVDKFVGIK-------DEDQLEAFLKK 163
Cdd:cd02987  143 KGGELIGNFVRVTedlgedfDAEDLESFLVE 173

Thioredoxin-like domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578837158   78 ETPVVVDFHAQWCGPCKILGPRLEKMVA-----KQHGKVVMAKV-----------DIDDHTDLAIEYEVSAVPTVLaMKN 141
Cdd:pfam13098   4 GKPVLVVFTDPDCPYCKKLKKELLEDPDvtvylGPNFVFIAVNIwcakevakaftDILENKELGRKYGVRGTPTIV-FFD 82

                          90       100
                  ....*....|....*....|.
gi 578837158  142 GD-VVDKFVGIKDEDQLEAFL 161
Cdd:pfam13098  83 GKgELLRLPGYVPAEEFLALL 103

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 578837158  80 PVVVDFHAQWCGPCKILGPRLEKMvAKQHGKVVM----------------------AKVDIDDHTDLAIEYEVSAVP-TV 136
Cdd:cd03010   27 PYLLNVWASWCAPCREEHPVLMAL-ARQGRVPIYginykdnpenalawlarhgnpyAAVGFDPDGRVGIDLGVYGVPeTF 105

                         90       100
                 ....*....|....*....|..
gi 578837158 137 LAMKNGDVVDKFVGIKDEDQLE 158
Cdd:cd03010  106 LIDGDGIIRYKHVGPLTPEVWE 127

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.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578837158  72 DRVVNSETPVVVDFHAQWCGPCKILGPRLEKMVAKQHGKVV-MAKVDIDDHTDLAiEYEVSAVPTVLAMKNGDVVDKFVG 150
Cdd:cd02948   11 EELLSNKGLTVVDVYQEWCGPCKAVVSLFKKIKNELGDDLLhFATAEADTIDTLK-RYRGKCEPTFLFYKNGELVAVIRG 89

Thioredoxin (TRX)-Glutaredoxin (GRX)-like family; composed of archaeal and bacterial proteins that show similarity to both TRX and GRX, including the C-terminal TRX-fold subdomain of Pyrococcus furiosus protein disulfide oxidoreductase (PfPDO). All members contain a redox-active CXXC motif and may function as PDOs. The archaeal proteins Mj0307 and Mt807 show structures more similar to GRX, but activities more similar to TRX. Some members of the family are similar to PfPDO in that they contain a second CXXC motif located in a second TRX-fold subdomain at the N-terminus; the superimposable N- and C-terminal TRX subdomains form a compact structure. PfPDO is postulated to be the archaeal counterpart of bacterial DsbA and eukaryotic protein disulfide isomerase (PDI). The C-terminal CXXC motif of PfPDO is required for its oxidase, reductase and isomerase activities. Also included in the family is the C-terminal TRX-fold subdomain of the N-terminal domain (NTD) of bacterial AhpF, which has a similar fold as PfPDO with two TRX-fold subdomains but without the second CXXC motif.

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                 ....*....|....*....|....*....|....*....|....*...
gi 578837158 103 MVAKQHGKVVMAKVDIDDHTDLAIEYEVSAVPTVLAmkNGDVVdkFVG 150
Cdd:cd02973   23 RIAALNPNISAEMIDAAEFPDLADEYGVMSVPAIVI--NGKVE--FVG 66

Phosducin (Phd)-like family, Viral inhibitor of apoptosis (IAP)-associated factor (VIAF) subfamily; VIAF is a Phd-like protein that functions in caspase activation during apoptosis. It was identified as an IAP binding protein through a screen of a human B-cell library using a prototype IAP. VIAF lacks a consensus IAP binding motif and while it does not function as an IAP antagonist, it still plays a regulatory role in the complete activation of caspases. VIAF itself is a substrate for IAP-mediated ubiquitination, suggesting that it may be a target of IAPs in the prevention of cell death. The similarity of VIAF to Phd points to a potential role distinct from apoptosis regulation. Phd functions as a cytosolic regulator of G protein by specifically binding to G protein betagamma (Gbg)-subunits. 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.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578837158  67 GPDFQDRVVN--SETPVVVDFHAQWCGPCKILGPRLEKMvAKQHGKVvmaK-VDIDDHTdlAIE-YEVSAVPTVLAMKNG 142
Cdd:cd02988   89 KPDYVREVTEasKDTWVVVHLYKDGIPLCRLLNQHLSEL-ARKFPDT---KfVKIISTQ--CIPnYPDKNLPTILVYRNG 162

                         90       100
                 ....*....|....*....|....*....
gi 578837158 143 DVVDKFVGIKDE-------DQLEAFLKKL 164
Cdd:cd02988  163 DIVKQFIGLLEFggmnttmEDLEWLLVQV 191