glutaredoxin 1; Provisional

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 489125561  1 MFAVIFGRPGCPYCVRAKELAEKLSSEHDDFNFRYIDIHAEGITKADLEKTVGKPVETVPQIFVDQKHIGGCTDFEAWAK 80
Cdd:PRK11200  1 MFVVIFGRPGCPYCVRAKELAEKLSEERDDFDYRYVDIHAEGISKADLEKTVGKPVETVPQIFVDQKHIGGCTDFEAYVK 80

                ....*
gi 489125561 81 ENMNL 85
Cdd:PRK11200 81 ENLGL 85

glutaredoxin 1; Provisional

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 489125561  1 MFAVIFGRPGCPYCVRAKELAEKLSSEHDDFNFRYIDIHAEGITKADLEKTVGKPVETVPQIFVDQKHIGGCTDFEAWAK 80
Cdd:PRK11200  1 MFVVIFGRPGCPYCVRAKELAEKLSEERDDFDYRYVDIHAEGISKADLEKTVGKPVETVPQIFVDQKHIGGCTDFEAYVK 80

                ....*
gi 489125561 81 ENMNL 85
Cdd:PRK11200 81 ENLGL 85

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 489125561  4 VIFGRPGCPYCVRAKELAEKLssehdDFNFRYIDIHAEGITKADLEKTVGKPveTVPQIFVDQKHIGGCTDFEAWAK 80
Cdd:cd02066   3 VVFSKSTCPYCKRAKRLLESL-----GIEFEEIDILEDGELREELKELSGWP--TVPQIFINGEFIGGYDDLKALHE 72

Glutaredoxin;

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 489125561   4 VIFGRPGCPYCVRAKELAEKLssehdDFNFRYIDIHAEGITKADLEKTVGKPveTVPQIFVDQKHI 69
Cdd:pfam00462  2 VLYTKPTCPFCKRAKRLLKSL-----GVDFEEIDVDEDPEIREELKELSGWP--TVPQVFIDGEHI 60

UXX-star (seleno)protein family 1;

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 489125561  4 VIFGRPGCPYCVRAKE-LAEKlssehddfnFRYIDIHAEgitKADLEK--TVGKPVETVPQIFVDQK 67
Cdd:NF041114  2 IIYGKDTCPYTRAAREaYAEK---------AEYIDVLKD---PEKLEEmlELSGGVRRVPVIVEDGK 56

glutaredoxin 1; Provisional

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 489125561  1 MFAVIFGRPGCPYCVRAKELAEKLSSEHDDFNFRYIDIHAEGITKADLEKTVGKPVETVPQIFVDQKHIGGCTDFEAWAK 80
Cdd:PRK11200  1 MFVVIFGRPGCPYCVRAKELAEKLSEERDDFDYRYVDIHAEGISKADLEKTVGKPVETVPQIFVDQKHIGGCTDFEAYVK 80

                ....*
gi 489125561 81 ENMNL 85
Cdd:PRK11200 81 ENLGL 85

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 489125561  4 VIFGRPGCPYCVRAKELAEKLssehdDFNFRYIDIHAEGITKADLEKTVGKPveTVPQIFVDQKHIGGCTDFEAWAK 80
Cdd:cd02066   3 VVFSKSTCPYCKRAKRLLESL-----GIEFEEIDILEDGELREELKELSGWP--TVPQIFINGEFIGGYDDLKALHE 72

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 489125561  4 VIFGRPGCPYCVRAKELAEKLSSEHDDFNfryIDIHAEG--ITKAdLEKTVGKPveTVPQIFVDQKHIGGCTDFEA 77
Cdd:cd03419   3 VVFSKSYCPYCKRAKSLLKELGVKPAVVE---LDQHEDGseIQDY-LQELTGQR--TVPNVFIGGKFIGGCDDLMA 72

Glutaredoxin;

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 489125561   4 VIFGRPGCPYCVRAKELAEKLssehdDFNFRYIDIHAEGITKADLEKTVGKPveTVPQIFVDQKHI 69
Cdd:pfam00462  2 VLYTKPTCPFCKRAKRLLKSL-----GVDFEEIDVDEDPEIREELKELSGWP--TVPQVFIDGEHI 60

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 489125561  2 FAVIFGRPGCPYCVRAKE-LAEKlssehddfNFRYIDIH-AEGITKADLEKTVGKpvETVPQIFVDQKHIGGCTDFEAW 78
Cdd:cd03029   2 SVSLFTKPGCPFCARAKAaLQEN--------GISYEEIPlGKDITGRSLRAVTGA--MTVPQVFIDGELIGGSDDLEKY 70

Glutaredoxin-family domain; This C-terminal domain with homology to glutaredoxin is fused to an N-terminal peroxiredoxin-like domain.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 489125561   4 VIFGRPGCPYCVRAKE-LAEKlssehddfNFRYIDIH-AEGITKADLEKTVGKpvETVPQIFVDQKHIGGCTDFEAW 78
Cdd:TIGR02190 11 VVFTKPGCPFCAKAKAtLKEK--------GYDFEEIPlGNDARGRSLRAVTGA--TTVPQVFIGGKLIGGSDELEAY 77

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 489125561  4 VIFGRPGCPYCVRAKELAEKLSSEHDDFNfryIDIHAEgiTKADLEKTVGKpvETVPQIFVDQKHIGGCTDFE 76
Cdd:cd03027   4 TIYSRLGCEDCTAVRLFLREKGLPYVEIN---IDIFPE--RKAELEERTGS--SVVPQIFFNEKLVGGLTDLK 69

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
                ....*....|....*....|....*....|....*....|....*...
gi 489125561  4 VIFGRPGCPYCVRAKE-LAEKlssehdDFNFRYIDIHAEGITKADLEK 50
Cdd:NF041212  2 VIYTKPGCPYCAAAKEdLARR------GIPFEEIDVSKDPEALEEMLR 43

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        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 489125561  4 VIFGRPGCPYCVRAKELAEKLSsehddFNFRYIDI--HAEGItkADLEKTVGKPveTVPQIFVDQKHIGG 71
Cdd:cd02976   3 TVYTKPDCPYCKATKRFLDERG-----IPFEEVDVdeDPEAL--EELKKLNGYR--SVPVVVIGDEHLSG 63

Glutaredoxin-like protein, YruB-family; This glutaredoxin-like protein family contains the conserved CxxC motif and includes the Clostridium pasteurianum protein YruB which has been cloned from a rubredoxin operon. Somewhat related to NrdH, it is unknown whether this protein actually interacts with glutathione/glutathione reducatase, or, like NrdH, some other reductant system.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 489125561   4 VIFGRPGCPYCVRAKELAEKLSSEhddfnFRYIDIHAEGITKADLEKTVGKpvETVPQIFVDQKHIGG 71
Cdd:TIGR02196  3 KVYTTPWCPPCVKAKEYLTSKGVA-----FEEIDVEKDAAAREELLKVYGQ--RGVPVIVIGHKIVVG 63

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
                ....*....|....*....|....*....|....*
gi 489125561  4 VIFGRPGCPYCVRAKELAEKLSSEHDDFNFRYIDI 38
Cdd:cd02947  15 VDFWAPWCGPCKAIAPVLEELAEEYPKVKFVKVDV 49

Thioredoxin-like domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 489125561    2 FAVIFGRPGCPYCVR-AKELAEKLS---SEHDDFNFRYIDI-----HAEGITKADLEKTVGK--PVETVPQI-FVDQK-- 67
Cdd:pfam13098   7 VLVVFTDPDCPYCKKlKKELLEDPDvtvYLGPNFVFIAVNIwcakeVAKAFTDILENKELGRkyGVRGTPTIvFFDGKge 86

                          90
                  ....*....|....*
gi 489125561   68 --HIGGCTDFEAWAK 80
Cdd:pfam13098  87 llRLPGYVPAEEFLA 101

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 489125561  4 VIF--GRPGCPYCVRAKELAEKLSSEHDDFnfRYIDIHAEGITKADLEKTVGKPveTVPQIFVDQKHIGGC 72
Cdd:cd03028  11 VLFmkGTPEEPRCGFSRKVVQILNQLGVDF--GTFDILEDEEVRQGLKEYSNWP--TFPQLYVNGELVGGC 77