Glutaredoxin (GRX) family, GRX human class 1 and 2 (h_1_2)-like subfamily; composed of proteins similar to human 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 human GRX1 and GRX2, which are members of this subfamily. Also included in this subfamily are the N-terminal GRX domains of proteins similar to human thioredoxin reductase 1 and 3.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11560105  14 KVVVFIKPTCPYCRKTQEILSQLPFKRGLLEfVDITAtnNTNAIQDYLQQLTGARTVPRVFIGKDCIGGCSDLLSMQQNG 93
Cdd:cd03419   1 PVVVFSKSYCPYCKRAKSLLKELGVKPAVVE-LDQHE--DGSEIQDYLQELTGQRTVPNVFIGGKFIGGCDDLMALHKSG 77

                ..
gi 11560105  94 EL 95
Cdd:cd03419  78 KL 79

Glutaredoxin;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 11560105    15 VVVFIKPTCPYCRKTQEILSQLPFKrglLEFVDITatnNTNAIQDYLQQLTGARTVPRVFIGKDCI 80
Cdd:pfam00462   1 VVLYTKPTCPFCKRAKRLLKSLGVD---FEEIDVD---EDPEIREELKELSGWPTVPQVFIDGEHI 60

Uxx-star family glutaredoxin-like (seleno)protein; A number of proteins with glutaredoxin-like folds, a length of about 75 amino acids, and a CxxC, C/UxxT, or CxxS motif near the N-terminus end with a UXX-COOH motif. That final motif typically is missed during coding region feature prediction by genome annotation pipelines. This HMM covers proteins from several distinctive families with this feature. The seed alignment illustrates the final selenocysteine or aligned Cys or Ser residues, but the HMM also hits proteins that lack an equivalent motif at the C-terminus. This C-terminal selenocysteine-containing motif has not yet been described in the literature.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 11560105   15 VVVFIKPTCPYCRKTQEILSqlpfKRGlLEFVDITATNNTNAIQDyLQQLTGA-RTVP 71
Cdd:NF041212   1 VVIYTKPGCPYCAAAKEDLA----RRG-IPFEEIDVSKDPEALEE-MLRLTGGeRIVP 52

Glutaredoxin (GRX) family, GRX human class 1 and 2 (h_1_2)-like subfamily; composed of proteins similar to human 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 human GRX1 and GRX2, which are members of this subfamily. Also included in this subfamily are the N-terminal GRX domains of proteins similar to human thioredoxin reductase 1 and 3.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11560105  14 KVVVFIKPTCPYCRKTQEILSQLPFKRGLLEfVDITAtnNTNAIQDYLQQLTGARTVPRVFIGKDCIGGCSDLLSMQQNG 93
Cdd:cd03419   1 PVVVFSKSYCPYCKRAKSLLKELGVKPAVVE-LDQHE--DGSEIQDYLQELTGQRTVPNVFIGGKFIGGCDDLMALHKSG 77

                ..
gi 11560105  94 EL 95
Cdd:cd03419  78 KL 79

Glutaredoxin (GRX) family; composed of GRX, 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 human GRX1 and GRX2, as well as E. coli GRX1 and GRX3, which are members of this family. E. coli GRX2, however, is a 24-kDa protein that belongs to the GSH S-transferase (GST) family.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 11560105  14 KVVVFIKPTCPYCRKTQEILSQLPFKrglLEFVDITATNntnAIQDYLQQLTGARTVPRVFIGKDCIGGCSDLLSMQQ 91
Cdd:cd02066   1 KVVVFSKSTCPYCKRAKRLLESLGIE---FEEIDILEDG---ELREELKELSGWPTVPQIFINGEFIGGYDDLKALHE 72

Glutaredoxin;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 11560105    15 VVVFIKPTCPYCRKTQEILSQLPFKrglLEFVDITatnNTNAIQDYLQQLTGARTVPRVFIGKDCI 80
Cdd:pfam00462   1 VVLYTKPTCPFCKRAKRLLKSLGVD---FEEIDVD---EDPEIREELKELSGWPTVPQVFIDGEHI 60

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        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11560105  14 KVVVFIKPTCPYCRKTQEILSqlpfKRGLlEFVDITATNNTNAIQDYLQQLTGARTVPRVFIGKDCIGGCSDLLSMQQNG 93
Cdd:cd03418   1 KVEIYTKPNCPYCVRAKALLD----KKGV-DYEEIDVDGDPALREEMINRSGGRRTVPQIFIGDVHIGGCDDLYALERKG 75

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 11560105  15 VVVFIKPTCPYCRKTQEILsqlpfKRGLLEFVDITATNNTNAIQdyLQQLTGARTVPRVFIGKDCIGGCSDL 86
Cdd:cd03029   3 VSLFTKPGCPFCARAKAAL-----QENGISYEEIPLGKDITGRS--LRAVTGAMTVPQVFIDGELIGGSDDL 67

glutaredoxin 1; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 11560105   14 KVVVFIKPTCPYCRKTQEILSQLPFKRGLLEF--VDITATNNTNAiqDyLQQLTG--ARTVPRVFIGKDCIGGCSD 85
Cdd:PRK11200   2 FVVIFGRPGCPYCVRAKELAEKLSEERDDFDYryVDIHAEGISKA--D-LEKTVGkpVETVPQIFVDQKHIGGCTD 74

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 11560105  14 KVVVFIKPTCPYCRKTQEILSqlpfKRGlLEFVDITATNNTNAIqDYLQQLTGARTVPRVFIGKD 78
Cdd:cd02976   1 EVTVYTKPDCPYCKATKRFLD----ERG-IPFEEVDVDEDPEAL-EELKKLNGYRSVPVVVIGDE 59

Glutaredoxin (GRX) family, PKC-interacting cousin of TRX (PICOT)-like subfamily; composed of PICOT and GRX-PICOT-like proteins. The non-PICOT members of this family contain only the GRX-like domain, whereas PICOT contains an N-terminal TRX-like domain followed by one to three GRX-like domains. It is interesting to note that PICOT from plants contain three repeats of the GRX-like domain, metazoan proteins (except for insect) have two repeats, while fungal sequences contain only one copy of the domain. PICOT is a protein that interacts with protein kinase C (PKC) theta, a calcium independent PKC isoform selectively expressed in skeletal muscle and T lymphocytes. PICOT inhibits the activation of c-Jun N-terminal kinase and the transcription factors, AP-1 and NF-kB, induced by PKC theta or T-cell activating stimuli. Both GRX and TRX domains of PICOT are required for its activity. Characterized non-PICOT members of this family include CXIP1, a CAX-interacting protein in Arabidopsis thaliana, and PfGLP-1, a GRX-like protein from Plasmodium falciparum.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11560105  10 IQSGKVVVFIK-----PTCPYCRKTQEILSQLPFKrglLEFVDITATNNtnaIQDYLQQLTGARTVPRVFIGKDCIGGCS 84
Cdd:cd03028   5 IKENPVVLFMKgtpeePRCGFSRKVVQILNQLGVD---FGTFDILEDEE---VRQGLKEYSNWPTFPQLYVNGELVGGCD 78

                        90
                ....*....|.
gi 11560105  85 DLLSMQQNGEL 95
Cdd:cd03028  79 IVKEMHESGEL 89

Glutaredoxin, GrxA 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 model includes the E. coli glyutaredoxin GrxA which appears to have primary responsibility for the reduction of ribonucleotide reductase.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 11560105    15 VVVFIKPTCPYCRKTQEILSQLPFKRGLLEF--VDITATNNTNAiqdYLQQLTG--ARTVPRVFIGKDCIGGCSD 85
Cdd:TIGR02183   2 VVIFGRPGCPYCVRAKQLAEKLAIERADFEFryIDIHAEGISKA---DLEKTVGkpVETVPQIFVDEKHVGGCTD 73

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 11560105  13 GKVVVFIKPTCPYCRKTQEILSQLPFKrglleFVDITaTNNTNAIQDYLQQLTGARTVPRVFIGKDCIGGCSDLLSM 89
Cdd:cd03027   1 GRVTIYSRLGCEDCTAVRLFLREKGLP-----YVEIN-IDIFPERKAELEERTGSSVVPQIFFNEKLVGGLTDLKSL 71

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
                ....*....|....*....|....*....|....*....|....*....|...
gi 11560105  58 QDYLQQLTGAR----TVPRVFIGKDCIGGCSDLLSMQQNGELTARLKQIGALQ 106
Cdd:cd03031  45 REELRELLGAElkavSLPRVFVDGRYLGGAEEVLRLNESGELRKLLKGIRARA 97

DsbA family, DsbC and DsbG subfamily; V-shaped homodimeric proteins containing a redox active CXXC motif imbedded in a TRX fold. They function as protein disulfide isomerases and chaperones in the bacterial periplasm to correct non-native disulfide bonds formed by DsbA and prevent aggregation of incorrectly folded proteins. DsbC and DsbG are kept in their reduced state by the cytoplasmic membrane protein DsbD, which utilizes the TRX/TRX reductase system in the cytosol as a source of reducing equivalents. DsbG differ from DsbC in that it has a more limited substrate specificity, and it may preferentially act later in the folding process to catalyze disulfide rearrangements in folded or partially folded proteins. Also included in the alignment is the predicted protein TrbB, whose gene was sequenced from the enterohemorrhagic E. coli type IV pilus gene cluster, which is required for efficient plasmid transfer.

                        10
                ....*....|....*
gi 11560105  14 KVVVFIKPTCPYCRK 28
Cdd:cd03020  80 VVYVFTDPDCPYCRK 94

Thioredoxin-like domain;

                          10        20
                  ....*....|....*....|....*....
gi 11560105    11 QSGK--VVVFIKPTCPYCRKTQEILSQLP 37
Cdd:pfam13098   2 GNGKpvLVVFTDPDCPYCKKLKKELLEDP 30