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 82617632 108 HRESNTAGIDIFSKFSAYIKNTKQQNNAALERGLTKALKKLDDYLNTPLPEEIDANTCGEDKGSRRKFLDGDELTLADCN 187
Cdd:cd10297   1 HRESNTAGIDIFSKFSAYIKNTKQQANAALEKGLTKALKKLDDYLNTPLPEEIDADSTEEEKVSNRKFLDGDELTLADCN 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 82617632 188 LLPKLHVVKIVAKKYRNYDIPAEMTGLWRYLKNAYARDEFTNTCAADSEIELAYADVAKRL 248
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 82617632    32 CPFSQRLFMILWLKGVVFNVTTVDL--KRKPADLHNLAPGTHPPFLTF-NGDVKTDVNKIEEFLEET 95
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 82617632 108 HRESNTAGIDIFSKFSAYIKNTKQQNNAALERGLTKALKKLDDYLNTPLPEEIDANTCGEDKGSRRKFLDGDELTLADCN 187
Cdd:cd10297   1 HRESNTAGIDIFSKFSAYIKNTKQQANAALEKGLTKALKKLDDYLNTPLPEEIDADSTEEEKVSNRKFLDGDELTLADCN 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 82617632 188 LLPKLHVVKIVAKKYRNYDIPAEMTGLWRYLKNAYARDEFTNTCAADSEIELAYADVAKRL 248
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 82617632 108 HRESNTAGIDIFSKFSAYIKNTKQQNNAALERGLTKALKKLDDYLNTPLPEEIDANTCGEDKGSRRKFLDGDELTLADCN 187
Cdd:cd10301   1 HPESNSAGNDVFAKFSAFIKNPRKDANENLEKNLLKALRKLDNYLNTPLPDEIDAYSTEDITVSDRKFLDGNELTLADCN 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 82617632 188 LLPKLHVVKIVAKKYRNYDIPAEMTGLWRYLKNAYARDEFTNTCAADSEIELAYADVAKR 247
Cdd:cd10301  81 LLPKLHIIKVVAKKYRNFEFPTEMTGIWRYLNNAYARDEFTNTCPADQEIEYAYSDVAKR 140

C-terminal, alpha helical domain of Chloride Intracellular Channel 2; Glutathione S-transferase (GST) C-terminal domain family, Chloride Intracellular Channel (CLIC) 2 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. CLIC2 contains an intramolecular disulfide bond and exists as a monomer regardless of redox conditions, in contrast to CLIC1 which forms a dimer under oxidizing conditions. It is expressed in most tissues except the brain, and is highly expressed in the lung, spleen, and in cardiac and skeletal muscles. CLIC2 interacts with ryanodine receptors (cardiac RyR2 and skeletal RyR1) and modulates their activity, suggesting that CLIC2 may function in the regulation of calcium release and signaling in cardiac and skeletal muscles.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82617632 108 HRESNTAGIDIFSKFSAYIKNTkQQNNAALERGLTKALKKLDDYLNTPLPEEIDANTCGEDKGSRRKFLDGDELTLADCN 187
Cdd:cd10298   1 YKESFDVGSDIFAKFSAYIKNS-PENNANQEKALLREFKRLDDYLNTPLPEEIDHDSAENITVSKRKFLDGDRLTLADCN 79

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 82617632 188 LLPKLHVVKIVAKKYRNYDIPAEMTGLWRYLKNAYARDEFTNTCAADSEIELAYADVAK 246
Cdd:cd10298  80 LLPKLHVIKVAAKKYCDFDIPADFTGVWRYLNNAYEREEFSQTCPADIEIEKAYASVAK 138

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 82617632  11 DRDPEIELFVKAGIDGESIGNCPFSQRLFMILWLKGVVFNVTTVDLKRKPADLHNLAPGTHPPFLTFNGDVKTDVNKIEE 90
Cdd:cd03061   1 QEEPEIELFVKASSDGESIGNCPFCQRLFMVLWLKGVVFNVTTVDMKRKPEDLKDLAPGTQPPFLLYNGEVKTDNNKIEE 80

                        90
                ....*....|.
gi 82617632  91 FLEETLTPEKY 101
Cdd:cd03061  81 FLEETLCPPKY 91

glutathione dehydrogenase (ascorbate)

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82617632   16 IELFVKAGID-GESIGNCPFSQRLFMILWLKGVVFNVTTVDLKRKPADLHNLAPGTHPPFLTFNGDVKTDVNKIEEFLEE 94
Cdd:PLN02817  56 LEVCVKASLTvPNKLGDCPFCQRVLLTLEEKHLPYDMKLVDLTNKPEWFLKISPEGKVPVVKLDEKWVADSDVITQALEE 135

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82617632   95 tltpeKYPKLA-AKHRESNTAGIDIFSKFSAYIKNtkQQNNAALERGLTKALKKLDDYLNTPLPeeidantcgedkgsrr 173
Cdd:PLN02817 136 -----KYPDPPlATPPEKASVGSKIFSTFIGFLKS--KDPGDGTEQALLDELTSFDDYIKENGP---------------- 192

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 82617632  174 kFLDGDELTLADCNLLPKLHVVKIVAKKYRNYDIPAEMTGLWRYLKNAYARDEFTNTCAADSEI 237
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 82617632 110 ESNTAGIDIFSKFSAYIKnTKQQNNAAlERGLTKALKKLDDYLNTPLPeeidantcgedkgsrrkFLDGDELTLADCNLL 189
Cdd:cd03201   6 EFASVGSKIFSTFVTFLK-SKDANDGS-EQALLDELTALDEHLKTNGP-----------------FIAGEKITAVDLSLA 66

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*...
gi 82617632 190 PKLHVVKIVAKKYRNYDIPAEMTGLWRYLKNAYARDEFTNTCAADSEI 237
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 82617632  31 NCPFSQRLFMILWLKGVVFNVTTVDLKRKPA-DLHNLAPGTHPPFLTFNGDVKTDVNKIEEFLE 93
Cdd:cd00570   8 GSPRSLRVRLALEEKGLPYELVPVDLGEGEQeEFLALNPLGKVPVLEDGGLVLTESLAILEYLA 71

Glutathione S-transferase [Posttranslational modification, protein turnover, chaperones];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82617632  31 NCPFSQRLFMILWLKGVVFNVTTVDLKR---KPADLHNLAPGTHPPFLTFNGDVKTDVNKIEEFLEET-----LTPEkYP 102
Cdd:COG0625   9 PSPNSRRVRIALEEKGLPYELVPVDLAKgeqKSPEFLALNPLGKVPVLVDDGLVLTESLAILEYLAERypeppLLPA-DP 87

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82617632 103 KLAAKHRE-----SNTAGIDIFSKFSAYIKNTKQQNNAALERGLTKALKKLDDYLntplpeeidantcgedkgSRRKFLD 177
Cdd:COG0625  88 AARARVRQwlawaDGDLHPALRNLLERLAPEKDPAAIARARAELARLLAVLEARL------------------AGGPYLA 149

                       170       180       190       200       210
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 82617632 178 GDELTLADCNLLPKLHVVkivakkyRNYDIP-AEMTGLWRYLKNAYARDEFTNTCAAD 234
Cdd:COG0625 150 GDRFSIADIALAPVLRRL-------DRLGLDlADYPNLAAWLARLAARPAFQRALAAA 200

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 82617632  31 NCPFSQRLFMILWLKGVVFNVTTVDLKRKPADLHNLAPGTHPPFLTFNGDVKTDVNKIEEFLEE 94
Cdd:cd03059   8 DDVYSHRVRIVLAEKGVSVEIIDVDPDNPPEDLAELNPYGTVPTLVDRDLVLYESRIIMEYLDE 71

C-terminal, alpha helical domain of an unknown subfamily 9 of Glutathione S-transferases; Glutathione S-transferase (GST) C-terminal domain family, unknown subfamily 9; composed of uncharacterized proteins with similarity to 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. GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. The GST fold contains an N-terminal thioredoxin-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. GSH binds to the N-terminal domain while the hydrophobic substrate occupies a pocket in the C-terminal domain.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82617632 126 IKNTKQQNNAALERGLtKALKKLDDYlntplpeeidantcgedkgsrRKFLDGDELTLADCNLLPKLHVVKIVAKKYRNY 205
Cdd:cd10424  30 SPEIKEEVRKDLLRGI-AALARLARF---------------------APYVAGETFTLADCAAFVHLPLVALATKKFYGE 87

                        90
                ....*....|....
gi 82617632 206 DIPAEMTGLWRYLK 219
Cdd:cd10424  88 DFLADLPGAKAYLA 101

GST_N family, Class Omega subfamily; 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. They 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. Polymorphisms of the class Omega GST genes may be associated with the development of some types of cancer and the age-at-onset of both Alzheimer's and Parkinson's diseases.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 82617632  32 CPFSQRLFMILWLKGVVFNVTTVDLKRKPADLHNLAP-GTHPPFLTFNGDVKTDVNKIEEFLE 93
Cdd:cd03055  27 CPYAQRARLVLAAKNIPHEVININLKDKPDWFLEKNPqGKVPALEIDEGKVVYESLIICEYLD 89

C-terminal, alpha helical domain of the Glutathione S-transferase family; Glutathione S-transferase (GST) family, C-terminal alpha helical 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). 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 thioredoxin-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. GSH binds to the N-terminal domain while the hydrophobic substrate occupies a pocket in the C-terminal domain. 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, metaxins, stringent starvation protein A, and aminoacyl-tRNA synthetases.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82617632 122 FSAYIKNTKQQNNAALERGLTKALKKLDDYLNTplpeeidantcgedkgsrRKFLDGDELTLADCNLLPKLHVVKIVAKK 201
Cdd:cd00299  22 LEKVPLPKDEAAVEAAREELPALLAALEQLLAG------------------RPYLAGDQFSLADVALAPVLARLEALGPY 83

                        90
                ....*....|....*....
gi 82617632 202 yrnYDIPAEMTGLWRYLKN 220
Cdd:cd00299  84 ---YDLLDEYPRLKAWYDR 99