CHAC1_HUMAN
ID CHAC1_HUMAN Reviewed; 222 AA.
AC Q9BUX1; Q0VIA0;
DT 30-MAY-2006, integrated into UniProtKB/Swiss-Prot.
DT 25-APR-2018, sequence version 3.
DT 03-AUG-2022, entry version 150.
DE RecName: Full=Glutathione-specific gamma-glutamylcyclotransferase 1 {ECO:0000303|PubMed:27913623};
DE Short=Gamma-GCG 1 {ECO:0000303|PubMed:27913623};
DE EC=4.3.2.7 {ECO:0000269|PubMed:27913623};
DE AltName: Full=Blocks Notch protein {ECO:0000303|PubMed:22445366};
DE Short=Botch {ECO:0000303|PubMed:22445366};
DE AltName: Full=Cation transport regulator-like protein 1 {ECO:0000303|PubMed:19109178};
GN Name=CHAC1 {ECO:0000303|PubMed:19109178, ECO:0000312|HGNC:HGNC:28680};
GN Synonyms=BOTCH {ECO:0000303|PubMed:22445366};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RA Zheng J.M., Liu Z.H., Li L.S.;
RT "Cloning and analyzing of a new chaC like cDNA from human kidney.";
RL Submitted (JUL-2004) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16572171; DOI=10.1038/nature04601;
RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J.,
RA Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E.,
RA Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B.,
RA Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R.,
RA O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B.,
RA Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S.,
RA Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.;
RT "Analysis of the DNA sequence and duplication history of human chromosome
RT 15.";
RL Nature 440:671-675(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Liver, and Muscle;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP FUNCTION, INDUCTION, AND SUBCELLULAR LOCATION.
RX PubMed=19109178; DOI=10.4049/jimmunol.182.1.466;
RA Mungrue I.N., Pagnon J., Kohannim O., Gargalovic P.S., Lusis A.J.;
RT "CHAC1/MGC4504 is a novel proapoptotic component of the unfolded protein
RT response, downstream of the ATF4-ATF3-CHOP cascade.";
RL J. Immunol. 182:466-476(2009).
RN [5]
RP FUNCTION.
RX PubMed=22445366; DOI=10.1016/j.devcel.2012.02.011;
RA Chi Z., Zhang J., Tokunaga A., Harraz M.M., Byrne S.T., Dolinko A., Xu J.,
RA Blackshaw S., Gaiano N., Dawson T.M., Dawson V.L.;
RT "Botch promotes neurogenesis by antagonizing Notch.";
RL Dev. Cell 22:707-720(2012).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=27913623; DOI=10.1074/jbc.m116.727479;
RA Kaur A., Gautam R., Srivastava R., Chandel A., Kumar A., Karthikeyan S.,
RA Bachhawat A.K.;
RT "ChaC2, an enzyme for slow turnover of cytosolic glutathione.";
RL J. Biol. Chem. 292:638-651(2017).
CC -!- FUNCTION: Catalyzes the cleavage of glutathione into 5-oxo-L-proline
CC and a Cys-Gly dipeptide. Acts specifically on glutathione, but not on
CC other gamma-glutamyl peptides (PubMed:27913623). Glutathione depletion
CC is an important factor for apoptosis initiation and execution. Acts as
CC a pro-apoptotic component of the unfolded protein response pathway by
CC mediating the pro-apoptotic effects of the ATF4-ATF3-DDIT3/CHOP cascade
CC (PubMed:19109178). Negative regulator of Notch signaling pathway
CC involved in embryonic neurogenesis: acts by inhibiting Notch cleavage
CC by furin, maintaining Notch in an immature inactive form, thereby
CC promoting neurogenesis in embryos (PubMed:22445366).
CC {ECO:0000269|PubMed:19109178, ECO:0000269|PubMed:22445366,
CC ECO:0000269|PubMed:27913623}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=glutathione = 5-oxo-L-proline + L-cysteinylglycine;
CC Xref=Rhea:RHEA:47724, ChEBI:CHEBI:57925, ChEBI:CHEBI:58402,
CC ChEBI:CHEBI:61694; EC=4.3.2.7;
CC Evidence={ECO:0000269|PubMed:27913623};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=2.2 mM for glutathione {ECO:0000269|PubMed:27913623};
CC Note=kcat is 225.2 min(-1) for glutathione.
CC {ECO:0000269|PubMed:27913623};
CC -!- SUBUNIT: Interacts with NOTCH1 (via extracellular region).
CC {ECO:0000250|UniProtKB:Q8R3J5}.
CC -!- INTERACTION:
CC Q9BUX1; Q9BQY4: RHOXF2; NbExp=2; IntAct=EBI-751127, EBI-372094;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:19109178}.
CC Golgi apparatus, trans-Golgi network {ECO:0000250|UniProtKB:Q8R3J5}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9BUX1-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9BUX1-2; Sequence=VSP_038960;
CC -!- INDUCTION: Induced by chemical activators of the unfolded protein
CC response (UPR) such as tunicamycin, DTT and thapsigargin.
CC {ECO:0000269|PubMed:19109178}.
CC -!- SIMILARITY: Belongs to the gamma-glutamylcyclotransferase family. ChaC
CC subfamily. {ECO:0000305}.
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DR EMBL; AY702027; AAW23972.1; -; mRNA.
DR EMBL; AC020661; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC001683; AAH01683.1; -; mRNA.
DR EMBL; BC001847; AAH01847.1; -; mRNA.
DR EMBL; BC019625; AAH19625.1; -; mRNA.
DR CCDS; CCDS10070.3; -. [Q9BUX1-1]
DR CCDS; CCDS45233.1; -. [Q9BUX1-2]
DR RefSeq; NP_077016.2; NM_024111.4. [Q9BUX1-1]
DR AlphaFoldDB; Q9BUX1; -.
DR SMR; Q9BUX1; -.
DR BioGRID; 122541; 6.
DR IntAct; Q9BUX1; 1.
DR STRING; 9606.ENSP00000398105; -.
DR iPTMnet; Q9BUX1; -.
DR PhosphoSitePlus; Q9BUX1; -.
DR BioMuta; CHAC1; -.
DR DMDM; 294862423; -.
DR EPD; Q9BUX1; -.
DR jPOST; Q9BUX1; -.
DR MassIVE; Q9BUX1; -.
DR PaxDb; Q9BUX1; -.
DR PeptideAtlas; Q9BUX1; -.
DR PRIDE; Q9BUX1; -.
DR ProteomicsDB; 79141; -. [Q9BUX1-1]
DR ProteomicsDB; 79142; -. [Q9BUX1-2]
DR ABCD; Q9BUX1; 1 sequenced antibody.
DR Antibodypedia; 23207; 310 antibodies from 28 providers.
DR DNASU; 79094; -.
DR Ensembl; ENST00000444189.7; ENSP00000395466.3; ENSG00000128965.13. [Q9BUX1-2]
DR Ensembl; ENST00000617768.5; ENSP00000484644.2; ENSG00000128965.13. [Q9BUX1-1]
DR GeneID; 79094; -.
DR KEGG; hsa:79094; -.
DR MANE-Select; ENST00000617768.5; ENSP00000484644.2; NM_024111.6; NP_077016.3.
DR UCSC; uc001znh.2; human. [Q9BUX1-1]
DR CTD; 79094; -.
DR DisGeNET; 79094; -.
DR GeneCards; CHAC1; -.
DR HGNC; HGNC:28680; CHAC1.
DR HPA; ENSG00000128965; Tissue enhanced (pancreas, skeletal muscle).
DR MIM; 614587; gene.
DR neXtProt; NX_Q9BUX1; -.
DR OpenTargets; ENSG00000128965; -.
DR PharmGKB; PA142672119; -.
DR VEuPathDB; HostDB:ENSG00000128965; -.
DR eggNOG; KOG3182; Eukaryota.
DR GeneTree; ENSGT00390000003855; -.
DR HOGENOM; CLU_070703_2_2_1; -.
DR InParanoid; Q9BUX1; -.
DR OMA; RPECTAV; -.
DR OrthoDB; 1238273at2759; -.
DR PhylomeDB; Q9BUX1; -.
DR TreeFam; TF313048; -.
DR BioCyc; MetaCyc:ENSG00000128965-MON; -.
DR PathwayCommons; Q9BUX1; -.
DR Reactome; R-HSA-174403; Glutathione synthesis and recycling.
DR Reactome; R-HSA-9648895; Response of EIF2AK1 (HRI) to heme deficiency.
DR SignaLink; Q9BUX1; -.
DR BioGRID-ORCS; 79094; 7 hits in 1073 CRISPR screens.
DR ChiTaRS; CHAC1; human.
DR GenomeRNAi; 79094; -.
DR Pharos; Q9BUX1; Tbio.
DR PRO; PR:Q9BUX1; -.
DR Proteomes; UP000005640; Chromosome 15.
DR RNAct; Q9BUX1; protein.
DR Bgee; ENSG00000128965; Expressed in gastrocnemius and 146 other tissues.
DR ExpressionAtlas; Q9BUX1; baseline and differential.
DR Genevisible; Q9BUX1; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005802; C:trans-Golgi network; ISS:UniProtKB.
DR GO; GO:0003839; F:gamma-glutamylcyclotransferase activity; IBA:GO_Central.
DR GO; GO:0061928; F:glutathione specific gamma-glutamylcyclotransferase activity; IEA:UniProtKB-EC.
DR GO; GO:0005112; F:Notch binding; ISS:UniProtKB.
DR GO; GO:0006750; P:glutathione biosynthetic process; TAS:Reactome.
DR GO; GO:0006751; P:glutathione catabolic process; IBA:GO_Central.
DR GO; GO:0070059; P:intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; IMP:UniProtKB.
DR GO; GO:0045746; P:negative regulation of Notch signaling pathway; IMP:UniProtKB.
DR GO; GO:0010955; P:negative regulation of protein processing; IMP:UniProtKB.
DR GO; GO:0022008; P:neurogenesis; ISS:UniProtKB.
DR GO; GO:0007219; P:Notch signaling pathway; IEA:UniProtKB-KW.
DR GO; GO:0006986; P:response to unfolded protein; IEA:UniProtKB-KW.
DR CDD; cd06661; GGCT_like; 1.
DR InterPro; IPR006840; ChaC.
DR InterPro; IPR013024; GGCT-like.
DR InterPro; IPR036568; GGCT-like_sf.
DR PANTHER; PTHR12192; PTHR12192; 1.
DR Pfam; PF04752; ChaC; 1.
DR SUPFAM; SSF110857; SSF110857; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Apoptosis; Cytoplasm; Golgi apparatus; Lyase;
KW Neurogenesis; Notch signaling pathway; Reference proteome;
KW Unfolded protein response.
FT CHAIN 1..222
FT /note="Glutathione-specific gamma-glutamylcyclotransferase
FT 1"
FT /id="PRO_0000239010"
FT REGION 1..24
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 115
FT /note="Proton acceptor"
FT /evidence="ECO:0000250|UniProtKB:O75223"
FT BINDING 35..40
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O75223"
FT VAR_SEQ 104..148
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|Ref.1"
FT /id="VSP_038960"
FT CONFLICT 17
FT /note="P -> H (in Ref. 1; AAW23972)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 222 AA; 24418 MW; DDE5A288BADB079E CRC64;
MKQESAAPNT PPTSQSPTPS AQFPRNDGDP QALWIFGYGS LVWRPDFAYS DSRVGFVRGY
SRRFWQGDTF HRGSDKMPGR VVTLLEDHEG CTWGVAYQVQ GEQVSKALKY LNVREAVLGG
YDTKEVTFYP QDAPDQPLKA LAYVATPQNP GYLGPAPEEA IATQILACRG FSGHNLEYLL
RLADFMQLCG PQAQDEHLAA IVDAVGTMLP CFCPTEQALA LV
