Protein Disulfide Oxidoreductases and Other Proteins with a Thioredoxin fold; The thioredoxin (TRX)-like superfamily is 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 the families of TRX, protein disulfide isomerase (PDI), tlpA, glutaredoxin, NrdH redoxin, and bacterial Dsb proteins (DsbA, DsbC, DsbG, DsbE, DsbDgamma). Members of the superfamily that do not function as PDOs but contain a TRX-fold domain include phosducins, peroxiredoxins, 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 356576993 135 RISFFSRSNCRECCAVRRFFRERALRFVEINVDVFAEREKELRERTGSATVPKIFFGEKLIGGLVELNALR 205
Cdd:cd03027    2 RVTIYSRLGCEDCTAVRLFLREKGLPYVEINIDIFPERKAELEERTGSSVVPQIFFNEKLVGGLTDLKSLE 72

Glutaredoxin (GRX) family, Dishevelled, Egl-10, and Pleckstrin (DEP) subfamily; composed of uncharacterized proteins containing a GRX domain and additional domains DEP and DUF547, both of which have unknown functions. GRX is a glutathione (GSH) dependent reductase containing a redox active CXXC motif in a TRX fold. It has preference for mixed GSH disulfide substrates, in which it uses a monothiol mechanism where only the N-terminal cysteine is required. By altering the redox state of target proteins, GRX is involved in many cellular functions.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 356576993 135 RISFFSRSNCRECCAVRRFFRERALRFVEINVDVFAEREKELRERTGSATVPKIFFGEKLIGGLVELNALR 205
Cdd:cd03027    2 RVTIYSRLGCEDCTAVRLFLREKGLPYVEINIDIFPERKAELEERTGSSVVPQIFFNEKLVGGLTDLKSLE 72

Domain found in Dishevelled, Egl-10, and Pleckstrin (DEP); The DEP domain is responsible for mediating intracellular protein targeting and regulation of protein stability in the cell. The DEP domain is present in a number of signaling molecules, including Regulator of G protein Signaling (RGS) proteins, and has been implicated in membrane targeting. New findings in yeast, however, demonstrate a major role for a DEP domain in mediating the interaction of an RGS protein to the C-terminal tail of a GPCR, thus placing RGS in close proximity with its substrate G protein alpha subunit.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 356576993  257 RLPIQDRWMKMKIARNCFAGSELVELLVRHHGCA-PSKAVEIGKQLCKKHFIHHVFGE-NDFEEGNHFYRF 325
Cdd:pfam00610   1 GVKLKDRRKHLKTYPNCFTGSEAVDWLMDNLEIItREEAVELGQLLLDQGLIHHVGDKhGLFKDSYYFYRF 71

Glutaredoxin;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 356576993  136 ISFFSRSNCRECCAVRRFFRERALRFVEINVDVFAEREKELRERTGSATVPKIFFGEKLI 195
Cdd:pfam00462   1 VVLYTKPTCPFCKRAKRLLKSLGVDFEEIDVDEDPEIREELKELSGWPTVPQVFIDGEHI 60

Glutaredoxin, GrxC family; Glutaredoxins are thioltransferases (disulfide reductases) which utilize glutathione and NADPH as cofactors. Oxidized glutathione is regenerated by glutathione reductase. Together these components compose the glutathione system. Glutaredoxins utilize the CXXC motif common to thioredoxins and are involved in multiple cellular processes including protection from redox stress, reduction of critical enzymes such as ribonucleotide reductase and the generation of reduced sulfur for iron sulfur cluster formation. Glutaredoxins are capable of reduction of mixed disulfides of glutathione as well as the formation of glutathione mixed disulfides. This family of glutaredoxins includes the E. coli protein GrxC (Grx3) which appears to have a secondary role in reducing ribonucleotide reductase (in the absence of GrxA) possibly indicating a role in the reduction of other protein disulfides. [Energy metabolism, Electron transport]

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 356576993  136 ISFFSRSNCRECCAVRRFFRERALRFVEINVDVFAEREKELRERTGSATVPKIFFGEKLIGGLVELNALRKDGG 209
Cdd:TIGR02181   1 VTIYTKPYCPYCTRAKALLSSKGVTFTEIRVDGDPALRDEMMQRSGRRTVPQIFIGDVHVGGCDDLYALDREGK 74

Glutaredoxin (GRX) family, Dishevelled, Egl-10, and Pleckstrin (DEP) subfamily; composed of uncharacterized proteins containing a GRX domain and additional domains DEP and DUF547, both of which have unknown functions. GRX is a glutathione (GSH) dependent reductase containing a redox active CXXC motif in a TRX fold. It has preference for mixed GSH disulfide substrates, in which it uses a monothiol mechanism where only the N-terminal cysteine is required. By altering the redox state of target proteins, GRX is involved in many cellular functions.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 356576993 135 RISFFSRSNCRECCAVRRFFRERALRFVEINVDVFAEREKELRERTGSATVPKIFFGEKLIGGLVELNALR 205
Cdd:cd03027    2 RVTIYSRLGCEDCTAVRLFLREKGLPYVEINIDIFPERKAELEERTGSSVVPQIFFNEKLVGGLTDLKSLE 72

DEP domain, named after Dishevelled, Egl-10, and Pleckstrin, where this domain was first discovered. The function of this domain is still not clear, but it is believed to be important for the membrane association of the signaling proteins in which it is present. New studies show that the DEP domain of Sst2, a yeast RGS protein is necessary and sufficient for receptor interaction.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 356576993 249 RVVRVLRQRLPIQDRWMKMKIARNCFAGSELVELLVRHHGCA-PSKAVEIGKQLCKKHFIHHVFG-ENDFEEGNHFYR 324
Cdd:cd04371    4 RIMLDSDSGVPIKDRKYHLKTYPNCFTGSELVDWLLDNLEAItREEAVELGQALLKHGLIHHVSDdKHTFRDSYALYR 81

Domain found in Dishevelled, Egl-10, and Pleckstrin; Domain of unknown function present in signalling proteins that contain PH, rasGEF, rhoGEF, rhoGAP, RGS, PDZ domains. DEP domain in Drosophila dishevelled is essential to rescue planar polarity defects and induce JNK signalling (Cell 94, 109-118).

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 356576993   254 LRQRLPIQDRWMKMKIARNCFAGSELVELLVRHHGCA-PSKAVEIGKQLCKKHFIHHVFGEND--FEEGNHFYRF 325
Cdd:smart00049   1 PETGLKLRDRKYFLKTYPNCFTGSELVDWLMDNLEIIdREEAVHLGQLLLDEGLIHHVNGPNKhtFKDSKALYRF 75

Glutaredoxin [Posttranslational modification, protein turnover, chaperones];

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 356576993 135 RISFFSRSNCRECCAVRRFFRERALRFVEINVDVFAEREKELRERTGSATVPKIFFGEKLIGG 197
Cdd:COG0695    1 KVTLYTTPGCPYCARAKRLLDEKGIPYEEIDVDEDPEAREELRERSGRRTVPVIFIGGEHLGG 63

Glutaredoxin (GRX) family, GRX bacterial class 1 and 3 (b_1_3)-like subfamily; composed of bacterial GRXs, approximately 10 kDa in size, and proteins containing a GRX or GRX-like domain. GRX is a glutathione (GSH) dependent reductase, catalyzing the disulfide reduction of target proteins such as ribonucleotide reductase. It contains a redox active CXXC motif in a TRX fold and uses a similar dithiol mechanism employed by TRXs for intramolecular disulfide bond reduction of protein substrates. Unlike TRX, GRX has preference for mixed GSH disulfide substrates, in which it uses a monothiol mechanism where only the N-terminal cysteine is required. The flow of reducing equivalents in the GRX system goes from NADPH -> GSH reductase -> GSH -> GRX -> protein substrates. By altering the redox state of target proteins, GRX is involved in many cellular functions including DNA synthesis, signal transduction and the defense against oxidative stress. Different classes are known including E. coli GRX1 and GRX3, which are members of this subfamily.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 356576993 136 ISFFSRSNCRECCAVRRFFRERALRFVEINVDVFAEREKELRERTGS-ATVPKIFFGEKLIGGLVELNALRKDG 208
Cdd:cd03418    2 VEIYTKPNCPYCVRAKALLDKKGVDYEEIDVDGDPALREEMINRSGGrRTVPQIFIGDVHIGGCDDLYALERKG 75

DEP (Dishevelled, Egl-10, and Pleckstrin) domain found in Epac-like proteins. Epac (exchange proteins directly activated by cAMP) proteins are GEFs (guanine-nucleotide-exchange factors) for the small GTPases, Rap1 and Rap2. They are directly regulated by cyclic AMP, a second messenger that plays a role in the control of diverse cellular processes, such as cell adhesion and insulin secretion. Epac-like proteins share a common domain architecture, containing RasGEF, DEP and CAP-effector (cAMP binding) domains. The DEP domain is involved in membrane localization.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 356576993 248 GRVVR-VLRQRLP--IQDRWMKMKIARNCFAGSELVELLVRHHGCAPSK--AVEIGKQLCKKHFIHHVFGENDFEEGNHF 322
Cdd:cd04437    2 GRALRnAILSDAPhlIRDRKYHLRTYRQCCVGTELVDWLLQQSPCVQSRsqAVGMWQVLLEEGVLLHVDQELHFQDKYQF 81

                         90
                 ....*....|...
gi 356576993 323 YRFLEHEPLISKC 335
Cdd:cd04437   82 YRFSDDECSPAPL 94

NrdH-redoxin (NrdH) family; NrdH is a small monomeric protein with a conserved redox active CXXC motif within a TRX fold, characterized by a glutaredoxin (GRX)-like sequence and TRX-like activity profile. In vitro, it displays protein disulfide reductase activity that is dependent on TRX reductase, not glutathione (GSH). It is part of the NrdHIEF operon, where NrdEF codes for class Ib ribonucleotide reductase (RNR-Ib), an efficient enzyme at low oxygen levels. Under these conditions when GSH is mostly conjugated to spermidine, NrdH can still function and act as a hydrogen donor for RNR-Ib. It has been suggested that the NrdHEF system may be the oldest RNR reducing system, capable of functioning in a microaerophilic environment, where GSH was not yet available. NrdH from Corynebacterium ammoniagenes can form domain-swapped dimers, although it is unknown if this happens in vivo. Domain-swapped dimerization, which results in the blocking of the TRX reductase binding site, could be a mechanism for regulating the oxidation state of the protein.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 356576993 135 RISFFSRSNCRECCAVRRFFRERALRFVEINVDVFAEREKELRERTGSATVPKIFFGEKLIGG 197
Cdd:cd02976    1 EVTVYTKPDCPYCKATKRFLDERGIPFEEVDVDEDPEALEELKKLNGYRSVPVVVIGDEHLSG 63

Glutaredoxin (GRX) family, PRX5 hybrid subfamily; composed of hybrid proteins containing peroxiredoxin (PRX) and GRX domains, which is found in some pathogenic bacteria and cyanobacteria. PRXs are thiol-specific antioxidant (TSA) proteins that confer a protective antioxidant role in cells through their peroxidase activity in which hydrogen peroxide, peroxynitrate, and organic hydroperoxides are reduced and detoxified using reducing equivalents derived from either thioredoxin, glutathione, trypanothione and AhpF. GRX is a glutathione (GSH) dependent reductase, catalyzing the disulfide reduction of target proteins. PRX-GRX hybrid proteins from Haemophilus influenza and Neisseria meningitis exhibit GSH-dependent peroxidase activity. The flow of reducing equivalents in the catalytic cycle of the hybrid protein goes from NADPH -> GSH reductase -> GSH -> GRX domain of hybrid -> PRX domain of hybrid -> peroxide substrate.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 356576993 136 ISFFSRSNCRECCAVRRFFRERALRFVEINVDVFAeREKELRERTGSATVPKIFFGEKLIGglvelnalrkdGGEELERR 215
Cdd:cd03029    3 VSLFTKPGCPFCARAKAALQENGISYEEIPLGKDI-TGRSLRAVTGAMTVPQVFIDGELIG-----------GSDDLEKY 70

                 .
gi 356576993 216 L 216
Cdd:cd03029   71 F 71

glutaredoxin 3; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 356576993 136 ISFFSRSNCRECCAVRRFFRERALRFVEINVDVFAEREKELRERTGSATVPKIFFGEKLIGGLVELNALRKDGG 209
Cdd:PRK10638   4 VEIYTKATCPFCHRAKALLNSKGVSFQEIPIDGDAAKREEMIKRSGRTTVPQIFIDAQHIGGCDDLYALDARGG 77

DEP (Dishevelled, Egl-10, and Pleckstrin) domain found in dishevelled-like proteins. Dishevelled-like proteins play a key role in the transduction of the Wnt signal from the cell surface to the nucleus, which in turn is an important regulatory pathway for cellular development and growth. They contain an N-terminal DIX domain, a central PDZ domain, and a C-terminal DEP domain.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 356576993 250 VVRVLRQR---LPIQDR-WMKMKIArNCFAGSELVELLVRH-HGCAPSK-AVEIGKQLCKKHFIHHVFGENDFEE 318
Cdd:cd04438    3 IPRVMRRPdsgLEIKDRmWLKITIP-NSFIGSDLVDWLLSHvEGLTDRReARKYASSLLKLGYIRHTVNKITFSE 76

glutaredoxin-like protein NrdH;

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 356576993 134 MRISFFSRSNCRECCAVRRFFRERALRFVEINVDVFAEREKELRERtGSATVPKIFFGE 192
Cdd:PRK10329   1 MRITIYTRNDCVQCHATKRAMESRGFDFEMINVDRVPEAAETLRAQ-GFRQLPVVIAGD 58

DEP (Dishevelled, Egl-10, and Pleckstrin) domain found in BBRC3-like proteins. BBRC3, also known as DEPDC1B, is a DEP containing protein of unknown function.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 356576993 250 VVRVLRQRLPIQDRWMKMKIARNCFAGSELV----ELLVRHHGCAP----SKAVEIGKQLCKKHFIHHV---FGENDFEE 318
Cdd:cd04447    6 VTELFRAGMPLRKHRQHFKSYENCFTASEAVdwlhELLRSNSNFGPevtrQQTVQLLKKFLKNHVIEDIkgrWGKEDLED 85

                 ....*..
gi 356576993 319 GNHFYRF 325
Cdd:cd04447   86 NNHLYRF 92

DEP (Dishevelled, Egl-10, and Pleckstrin) domain found in GPR155-like proteins. GRP155-like proteins, also known as PGR22, contain an N-terminal permease domain, a central transmembrane region and a C-terminal DEP domain. They are orphan receptors of the class B G protein-coupled receptors. Their function is unknown.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 356576993 255 RQRLPIQDRWMKmKIARNCFAGSELVELLVRhHGCA--PSKAVEIGKQLCKKHFIHHVFGENDFEEGNHFYRF 325
Cdd:cd04443   13 RQDIVKDRRCGL-RTYKGVFCGCDLVSWLIE-VGLAqdRGEAVLYGRRLLQGGVLQHITNEHHFRDENLLYRF 83

Glutaredoxin (GRX) family, GRX-like domain containing protein subfamily; composed of uncharacterized eukaryotic proteins containing a GRX-like domain having only one conserved cysteine, aligning to the C-terminal cysteine of the CXXC motif of GRXs. This subfamily is predominantly composed of plant proteins. GRX is a glutathione (GSH) dependent reductase, catalyzing the disulfide reduction of target proteins via a redox active CXXC motif using a similar dithiol mechanism employed by TRXs. GRX has preference for mixed GSH disulfide substrates, in which it uses a monothiol mechanism where only the N-terminal cysteine is required. Proteins containing only the C-terminal cysteine are generally redox inactive.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 356576993 147 CCAVRRFFRERALRFVEINVDVFAEREKELRERTG----SATVPKIFFGEKLIGGLVELNALRKDGgeELERRLTAAVGE 222
Cdd:cd03031   19 CNNVRAILESFRVKFDERDVSMDSGFREELRELLGaelkAVSLPRVFVDGRYLGGAEEVLRLNESG--ELRKLLKGIRAR 96

                 ....*
gi 356576993 223 GPSAP 227
Cdd:cd03031   97 AGGGV 101