C-terminal, alpha helical domain of Chloride Intracellular Channel 5; Glutathione S-transferase (GST) C-terminal domain family, Chloride Intracellular Channel (CLIC) 5 subfamily; CLICs are auto-inserting, self-assembling intracellular anion channels involved in a wide variety of functions including regulated secretion, cell division, and apoptosis. They can exist in both water-soluble and membrane-bound states and are found in various vesicles and membranes, and they may play roles in the maintenance of these intracellular membranes. The membrane localization domain is present in the N-terminal part of the protein. Structures of soluble CLICs reveal that they adopt a fold similar to GSTs, containing an N-terminal domain with a thioredoxin fold and a C-terminal alpha helical domain. CLIC5 exists in two alternatively-spliced isoforms, CLIC5A or CLIC5B (also called p64). It is expressed at high levels in hair cell stereocilia and is associated with the actin cytoskeleton and ezrin. A recessive mutation in the CLIC5 gene in mice led to the lack of coordination and deafness, due to a defect in the basal region of the hair bundle causing stereocilia to degrade. CLIC5 is therefore essential for normal inner ear function. CLIC5 is also highly expressed in podocytes where it is colocalized with the ezrin/radixin/moesin (ERM) complex. It is essential for foot process integrity, and for podocyte morphology and function.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 569000001 342 HRESNTAGIDIFSKFSAYIKNTKQQNNAALERGLTKALRKLDDYLNSPLPEEIDTNTHGDEKGSQRKFLDGDELTLADCN 421
Cdd:cd10297    1 HRESNTAGIDIFSKFSAYIKNTKQQANAALEKGLTKALKKLDDYLNTPLPEEIDADSTEEEKVSNRKFLDGDELTLADCN 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 569000001 422 LLPKLHVVKIVAKKYRNYDIPAEMTGLWRYLKNAYARDEFTNTCAADSEIELAYADVARRL 482
Cdd:cd10297   81 LLPKLHVVKIVAKKYRNFEIPSDMTGVWRYLKNAYARDEFTNTCAADKEIELAYADVAKRL 141

Glutathione S-transferase, N-terminal domain; This family is closely related to pfam02798.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 569000001  266 CPFSQRLFMILWLKGVVFNVTTVDL--KRKPADLHNLAPGTHPPFLTF-NGDVKTDVNKIEEFLEET 329
Cdd:pfam13409   2 SPFSHRVRLALEEKGLPYEIELVDLdpKDKPPELLALNPLGTVPVLVLpDGTVLTDSLVILEYLEEL 68

C-terminal, alpha helical domain of Chloride Intracellular Channel 5; Glutathione S-transferase (GST) C-terminal domain family, Chloride Intracellular Channel (CLIC) 5 subfamily; CLICs are auto-inserting, self-assembling intracellular anion channels involved in a wide variety of functions including regulated secretion, cell division, and apoptosis. They can exist in both water-soluble and membrane-bound states and are found in various vesicles and membranes, and they may play roles in the maintenance of these intracellular membranes. The membrane localization domain is present in the N-terminal part of the protein. Structures of soluble CLICs reveal that they adopt a fold similar to GSTs, containing an N-terminal domain with a thioredoxin fold and a C-terminal alpha helical domain. CLIC5 exists in two alternatively-spliced isoforms, CLIC5A or CLIC5B (also called p64). It is expressed at high levels in hair cell stereocilia and is associated with the actin cytoskeleton and ezrin. A recessive mutation in the CLIC5 gene in mice led to the lack of coordination and deafness, due to a defect in the basal region of the hair bundle causing stereocilia to degrade. CLIC5 is therefore essential for normal inner ear function. CLIC5 is also highly expressed in podocytes where it is colocalized with the ezrin/radixin/moesin (ERM) complex. It is essential for foot process integrity, and for podocyte morphology and function.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 569000001 342 HRESNTAGIDIFSKFSAYIKNTKQQNNAALERGLTKALRKLDDYLNSPLPEEIDTNTHGDEKGSQRKFLDGDELTLADCN 421
Cdd:cd10297    1 HRESNTAGIDIFSKFSAYIKNTKQQANAALEKGLTKALKKLDDYLNTPLPEEIDADSTEEEKVSNRKFLDGDELTLADCN 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 569000001 422 LLPKLHVVKIVAKKYRNYDIPAEMTGLWRYLKNAYARDEFTNTCAADSEIELAYADVARRL 482
Cdd:cd10297   81 LLPKLHVVKIVAKKYRNFEIPSDMTGVWRYLKNAYARDEFTNTCAADKEIELAYADVAKRL 141

C-terminal, alpha helical domain of Chloride Intracellular Channel 6; Glutathione S-transferase (GST) C-terminal domain family, Chloride Intracellular Channel (CLIC) 6 subfamily; CLICs are auto-inserting, self-assembling intracellular anion channels involved in a wide variety of functions including regulated secretion, cell division, and apoptosis. They can exist in both water-soluble and membrane-bound states and are found in various vesicles and membranes, and they may play roles in the maintenance of these intracellular membranes. The membrane localization domain is present in the N-terminal part of the protein. Structures of soluble CLICs reveal that they adopt a fold similar to GSTs, containing an N-terminal domain with a thioredoxin fold and a C-terminal alpha helical domain. CLIC6 is expressed predominantly in the stomach, pituitary, and brain. It interacts with D2-like dopamine receptors directly and through scaffolding proteins. CLIC6 may be involved in the regulation of secretion, possibly through chloride ion transport regulation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 569000001 342 HRESNTAGIDIFSKFSAYIKNTKQQNNAALERGLTKALRKLDDYLNSPLPEEIDTNTHGDEKGSQRKFLDGDELTLADCN 421
Cdd:cd10301    1 HPESNSAGNDVFAKFSAFIKNPRKDANENLEKNLLKALRKLDNYLNTPLPDEIDAYSTEDITVSDRKFLDGNELTLADCN 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 569000001 422 LLPKLHVVKIVAKKYRNYDIPAEMTGLWRYLKNAYARDEFTNTCAADSEIELAYADVARR 481
Cdd:cd10301   81 LLPKLHIIKVVAKKYRNFEFPTEMTGIWRYLNNAYARDEFTNTCPADQEIEYAYSDVAKR 140

C-terminal, alpha helical domain of Chloride Intracellular Channels; Glutathione S-transferase (GST) C-terminal domain family, Chloride Intracellular Channel (CLIC) subfamily; composed of CLICs (CLIC1-6 in vertebrates), p64, parchorin, and similar proteins. They are auto-inserting, self-assembling intracellular anion channels involved in a wide variety of functions including regulated secretion, cell division, and apoptosis. They can exist in both water-soluble and membrane-bound states and are found in various vesicles and membranes, and they may play roles in the maintenance of these intracellular membranes. Biochemical studies of the Caenorhabditis elegans homolog, EXC-4, show that the membrane localization domain is present in the N-terminal part of the protein. CLICs display structural plasticity, with CLIC1 adopting two soluble conformations. The structure of soluble human CLIC1 reveals that it is monomeric and adopts a fold similar to GSTs, containing an N-terminal domain with a thioredoxin fold and a C-terminal alpha helical domain. Upon oxidation, the N-terminal domain of CLIC1 undergoes a structural change to form a non-covalent dimer stabilized by the formation of an intramolecular disulfide bond between two cysteines that are far apart in the reduced form. The CLIC1 dimer bears no similarity to GST dimers. The redox-controlled structural rearrangement exposes a large hydrophobic surface, which is masked by dimerization in vitro. In vivo, this surface may represent the docking interface of CLIC1 in its membrane-bound state. The two cysteines in CLIC1 that form the disulfide bond in oxidizing conditions are essential for dimerization and chloride channel activity, however, in other subfamily members, the second cysteine is not conserved.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 569000001 342 HRESNTAGIDIFSKFSAYIKNTKQQNNAALERGLTKALRKLDDYLNSplpeeidtnthgdekgSQRKFLDGDELTLADCN 421
Cdd:cd03198    1 NPEANTAGEDLFAKFSAYIKNKDPAADEALRKALLKELSKLDAYLSS----------------SSRKFLDGDTLTLADCN 64

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 569000001 422 LLPKLHVVKIVAKKYRNYDIPAEMTGLWRYLKNAYARDEFTNTCAADSEIELAYA 476
Cdd:cd03198   65 LLPKLHHIRVAGKAYKDFDIPDDFTGLWRYLKNAYETDEFTKTCPADQEIILHYK 119

GST_N family, Chloride Intracellular Channel (CLIC) subfamily; composed of CLIC1-5, p64, parchorin and similar proteins. They are auto-inserting, self-assembling intracellular anion channels involved in a wide variety of functions including regulated secretion, cell division and apoptosis. They can exist in both water-soluble and membrane-bound states, and are found in various vesicles and membranes. Biochemical studies of the C. elegans homolog, EXC-4, show that the membrane localization domain is present in the N-terminal part of the protein. The structure of soluble human CLIC1 reveals that it is monomeric and it adopts a fold similar to GSTs, containing an N-terminal domain with a TRX fold and a C-terminal alpha helical domain. Upon oxidation, the N-terminal domain of CLIC1 undergoes a structural change to form a non-covalent dimer stabilized by the formation of an intramolecular disulfide bond between two cysteines that are far apart in the reduced form. The CLIC1 dimer bears no similarity to GST dimers. The redox-controlled structural rearrangement exposes a large hydrophobic surface, which is masked by dimerization in vitro. In vivo, this surface may represent the docking interface of CLIC1 in its membrane-bound state. The two cysteines in CLIC1 that form the disulfide bond in oxidizing conditions are essential for dimerization and chloride channel activity, however, in other subfamily members, the second cysteine is not conserved.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 569000001 248 PEIFLFVKAGIDGESIGNCPFSQRLFMILWLKGVVFNVTTVDLKRKPADLHNLAPGTHPPFLTFNGDVKTDVNKIEEFLE 327
Cdd:cd03061    4 PEIELFVKASSDGESIGNCPFCQRLFMVLWLKGVVFNVTTVDMKRKPEDLKDLAPGTQPPFLLYNGEVKTDNNKIEEFLE 83

                 ....*...
gi 569000001 328 ETLTPEKY 335
Cdd:cd03061   84 ETLCPPKY 91

glutathione dehydrogenase (ascorbate)

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 569000001 243 AASSNPEIFLFVKAGID-GESIGNCPFSQRLFMILWLKGVVFNVTTVDLKRKPADLHNLAPGTHPPFLTFNGDVKTDVNK 321
Cdd:PLN02817  49 AITMSSPLEVCVKASLTvPNKLGDCPFCQRVLLTLEEKHLPYDMKLVDLTNKPEWFLKISPEGKVPVVKLDEKWVADSDV 128

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 569000001 322 IEEFLEEtltpeKYPKLA-AKHRESNTAGIDIFSKFSAYIKNtkQQNNAALERGLTKALRKLDDYLNSPLPeeidtnthg 400
Cdd:PLN02817 129 ITQALEE-----KYPDPPlATPPEKASVGSKIFSTFIGFLKS--KDPGDGTEQALLDELTSFDDYIKENGP--------- 192

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 569000001 401 dekgsqrkFLDGDELTLADCNLLPKLHVVKIVAKKYRNYDIPAEMTGLWRYLKNAYARDEFTNTCAADSEI 471
Cdd:PLN02817 193 --------FINGEKISAADLSLGPKLYHLEIALGHYKNWSVPDSLPFVKSYMKNIFSMESFVKTRALPEDV 255

C-terminal, alpha helical domain of Dehydroascorbate Reductase; Glutathione S-transferase (GST) C-terminal domain family, Dehydroascorbate Reductase (DHAR) subfamily; composed of plant-specific DHARs, which are monomeric enzymes catalyzing the reduction of DHA into ascorbic acid (AsA) using glutathione as the reductant. DHAR allows plants to recycle oxidized AsA before it is lost. AsA serves as a cofactor of violaxanthin de-epoxidase in the xanthophyll cycle and as an antioxidant in the detoxification of reactive oxygen species. Because AsA is the major reductant in plants, DHAR serves to regulate their redox state. It has been suggested that a significant portion of DHAR activity is plastidic, acting to reduce the large amounts of ascorbate oxidized during hydrogen peroxide scavenging by ascorbate peroxidase. DHAR contains a conserved cysteine in its active site and in addition to its reductase activity, shows thiol transferase activity similar to glutaredoxins.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 569000001 344 ESNTAGIDIFSKFSAYIKnTKQQNNAAlERGLTKALRKLDDYLNsplpeeidtnTHGdekgsqrKFLDGDELTLADCNLL 423
Cdd:cd03201    6 EFASVGSKIFSTFVTFLK-SKDANDGS-EQALLDELTALDEHLK----------TNG-------PFIAGEKITAVDLSLA 66

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 569000001 424 PKLHVVKIVAKKYRNYDIPAEMTGLWRYLKNAYARDEFTNTCAADSEI 471
Cdd:cd03201   67 PKLYHLRVALGHYKGWSVPESLTAVHKYMELLFSRESFKKTKAPDEMI 114

Glutathione S-transferase (GST) family, N-terminal domain; a large, diverse group of cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. In addition, GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. This family, also referred to as soluble GSTs, is the largest family of GSH transferases and is only distantly related to the mitochondrial GSTs (GSTK subfamily, a member of the DsbA family). Soluble GSTs bear no structural similarity to microsomal GSTs (MAPEG family) and display additional activities unique to their group, such as catalyzing thiolysis, reduction and isomerization of certain compounds. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. Based on sequence similarity, different classes of GSTs have been identified, which display varying tissue distribution, substrate specificities and additional specific activities. In humans, GSTs display polymorphisms which may influence individual susceptibility to diseases such as cancer, arthritis, allergy and sclerosis. Some GST family members with non-GST functions include glutaredoxin 2, the CLIC subfamily of anion channels, prion protein Ure2p, crystallins, metaxin 2 and stringent starvation protein A.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 569000001 265 NCPFSQRLFMILWLKGVVFNVTTVDLKRKPA-DLHNLAPGTHPPFLTFNGDVKTDVNKIEEFLE 327
Cdd:cd00570    8 GSPRSLRVRLALEEKGLPYELVPVDLGEGEQeEFLALNPLGKVPVLEDGGLVLTESLAILEYLA 71

GST_N family, Omega-like subfamily; composed of uncharacterized proteins with similarity to class Omega GSTs. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. Class Omega GSTs show little or no GSH-conjugating activity towards standard GST substrates. Instead, they catalyze the GSH dependent reduction of protein disulfides, dehydroascorbate and monomethylarsonate, activities which are more characteristic of glutaredoxins. Like Omega enzymes, proteins in this subfamily contain a conserved cysteine equivalent to the first cysteine in the CXXC motif of glutaredoxins, which is a redox active residue capable of reducing GSH mixed disulfides in a monothiol mechanism.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 569000001 266 CPFSQRLFMILWLKGVVFNVTTVDLKRKPADLHNLAP-GTHPPFLTFNGDVktdvnkIEEFLE 327
Cdd:cd03060    9 CPYAMRARMALLLAGITVELREVELKNKPAEMLAASPkGTVPVLVLGNGTV------IEESLD 65

GST_N family, Stringent starvation protein A (SspA) subfamily; SspA is a RNA polymerase (RNAP)-associated protein required for the lytic development of phage P1 and for stationary phase-induced acid tolerance of E. coli. It is implicated in survival during nutrient starvation. SspA adopts the GST fold with an N-terminal TRX-fold domain and a C-terminal alpha helical domain, but it does not bind glutathione (GSH) and lacks GST activity. SspA is highly conserved among gram-negative bacteria. Related proteins found in Neisseria (called RegF), Francisella and Vibrio regulate the expression of virulence factors necessary for pathogenesis.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 569000001 265 NCPFSQRLFMILWLKGVVFNVTTVDLKRKPADLHNLAPGTHPPFLTFNGDVKTDVNKIEEFLEE 328
Cdd:cd03059    8 DDVYSHRVRIVLAEKGVSVEIIDVDPDNPPEDLAELNPYGTVPTLVDRDLVLYESRIIMEYLDE 71

C-terminal, alpha helical domain of Class Omega-like Glutathione S-transferases; Glutathione S-transferase (GST) C-terminal domain family, Saccharomyces cerevisiae Omega-like subfamily; composed of three Saccharomyces cerevisiae GST omega-like (Gto) proteins, Gto1p, Gto2p (also known as Extracellular mutant protein 4 or ECM4p), and Gto3p, as well as similar uncharacterized proteins from fungi and bacteria. The three Saccharomyces cerevisiae Gto proteins are omega-class GSTs with low or no GST activity against standard substrates, but have glutaredoxin/thiol oxidoreductase and dehydroascorbate reductase activity through a single cysteine residue in the active site. Gto1p is located in the peroxisomes while Gto2p and Gto3p are cytosolic. The gene encoding Gto2p, called ECM4, is involved in cell surface biosynthesis and architecture. S. cerevisiae ECM4 mutants show increased amounts of the cell wall hexose, N-acetylglucosamine. More recently, global gene expression analysis shows that ECM4 is upregulated during genotoxic conditions and together with the expression profiles of 18 other genes could potentially differentiate between genotoxic and cytotoxic insults in yeast.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 569000001 375 LTKALRKLDDYLnsplpeeidtnthgdekgSQRKFLDGDELTLADCNLLPKL------HVV--KIVAKKYRNYdiPAemt 446
Cdd:cd03190   42 LFEALDKLEKRL------------------SKQPYLLGDRLTEADIRLFTTLirfdpvYHQhfKCNLKTIRDY--PN--- 98

                         90
                 ....*....|....*....
gi 569000001 447 gLWRYLKNAYARDEFTNTC 465
Cdd:cd03190   99 -LWRYLRRLYQNPGVFETT 116

Glutathione S-transferase C-terminal-like, alpha helical domain of the Gamma subunit of Elongation Factor 1B and similar proteins; Glutathione S-transferase (GST) C-terminal domain family, Gamma subunit of Elongation Factor 1B (EF1Bgamma) subfamily; EF1Bgamma is part of the eukaryotic translation elongation factor-1 (EF1) complex which plays a central role in the elongation cycle during protein biosynthesis. EF1 consists of two functionally distinct units, EF1A and EF1B. EF1A catalyzes the GTP-dependent binding of aminoacyl-tRNA to the ribosomal A site concomitant with the hydrolysis of GTP. The resulting inactive EF1A:GDP complex is recycled to the active GTP form by the guanine-nucleotide exchange factor EF1B, a complex composed of at least two subunits, alpha and gamma. Metazoan EFB1 contain a third subunit, beta. The EF1B gamma subunit contains a GST fold consisting of an N-terminal thioredoxin-fold domain and a C-terminal alpha helical domain. The GST-like domain of EF1Bgamma is believed to mediate the dimerization of the EF1 complex, which in yeast is a dimer of the heterotrimer EF1A:EF1Balpha:EF1Bgamma. In addition to its role in protein biosynthesis, EF1Bgamma may also display other functions. The recombinant rice protein has been shown to possess GSH conjugating activity. The yeast EF1Bgamma binds to membranes in a calcium dependent manner and is also part of a complex that binds to the msrA (methionine sulfoxide reductase) promoter suggesting a function in the regulation of its gene expression. Also included in this subfamily is the GST_C-like domain at the N-terminus of human valyl-tRNA synthetase (ValRS) and its homologs. Metazoan ValRS forms a stable complex with Elongation Factor-1H (EF-1H), and together, they catalyze consecutive steps in protein biosynthesis, tRNA aminoacylation and its transfer to EF.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 569000001 359 YIKNTKQQNNAALERgLTKALRKLDDYLNSplpeeidtnthgdekgsqRKFLDGDELTLAD----CNLLPKLHVV--KIV 432
Cdd:cd03181   30 IAPYNKKAVDKAKED-LKRALGVLEEHLLT------------------RTYLVGERITLADifvaSALLRGFETVldPEF 90

                 ....*.
gi 569000001 433 AKKYRN 438
Cdd:cd03181   91 RKKYPN 96