ATOX1_HUMAN
ID ATOX1_HUMAN Reviewed; 68 AA.
AC O00244; A8KAJ8; D3DQI2; Q2M1R6; Q56AP3;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1997, sequence version 1.
DT 03-AUG-2022, entry version 182.
DE RecName: Full=Copper transport protein ATOX1;
DE AltName: Full=Metal transport protein ATX1;
GN Name=ATOX1; Synonyms=HAH1;
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].
RC TISSUE=Liver;
RX PubMed=9083055; DOI=10.1074/jbc.272.14.9221;
RA Klomp L.W.J., Lin S.-J., Yuan D.S., Klausner R.D., Culotta V.C.,
RA Gitlin J.D.;
RT "Identification and functional expression of HAH1, a novel human gene
RT involved in copper homeostasis.";
RL J. Biol. Chem. 272:9221-9226(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=12594858; DOI=10.1186/1471-2156-4-4;
RA Liu P.-C., Koeller D.M., Kaler S.G.;
RT "Genomic organization of ATOX1, a human copper chaperone.";
RL BMC Genet. 4:4-4(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Uterus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [10]
RP INTERACTION WITH ATP7A.
RX PubMed=21667063; DOI=10.1007/s00018-011-0743-1;
RA Vonk W.I., de Bie P., Wichers C.G., van den Berghe P.V., van der Plaats R.,
RA Berger R., Wijmenga C., Klomp L.W., van de Sluis B.;
RT "The copper-transporting capacity of ATP7A mutants associated with Menkes
RT disease is ameliorated by COMMD1 as a result of improved protein
RT expression.";
RL Cell. Mol. Life Sci. 69:149-163(2012).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-47, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS), COPPER-BINDING SITES, AND
RP INTERACTION WITH ATP7B.
RX PubMed=10966647; DOI=10.1038/78999;
RA Wernimont A.K., Huffman D.L., Lamb A.L., O'Halloran T.V., Rosenzweig A.C.;
RT "Structural basis for copper transfer by the metallochaperone for the
RT Menkes/Wilson disease proteins.";
RL Nat. Struct. Biol. 7:766-771(2000).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 2-68, INTERACTION WITH ATP7A,
RP DOMAIN, AND MUTAGENESIS OF ARG-21; VAL-22 AND THR-58.
RX PubMed=19453293; DOI=10.1042/bj20090422;
RA Banci L., Bertini I., Calderone V., Della-Malva N., Felli I.C., Neri S.,
RA Pavelkova A., Rosato A.;
RT "Copper(I)-mediated protein-protein interactions result from suboptimal
RT interaction surfaces.";
RL Biochem. J. 422:37-42(2009).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (2.83 ANGSTROMS) OF 2-68 IN COMPLEX WITH COPPER,
RP MUTAGENESIS OF CYS-15, AND DOMAIN.
RX PubMed=31283225; DOI=10.1021/jacs.9b05550;
RA Lasorsa A., Nardella M.I., Rosato A., Mirabelli V., Caliandro R.,
RA Caliandro R., Natile G., Arnesano F.;
RT "Mechanistic and Structural Basis for Inhibition of Copper Trafficking by
RT Platinum Anticancer Drugs.";
RL J. Am. Chem. Soc. 141:12109-12120(2019).
CC -!- FUNCTION: Binds and deliver cytosolic copper to the copper ATPase
CC proteins. May be important in cellular antioxidant defense.
CC -!- SUBUNIT: Interacts with ATP7B (PubMed:10966647). Interacts with ATP7A
CC (PubMed:21667063, PubMed:19453293). {ECO:0000269|PubMed:10966647,
CC ECO:0000269|PubMed:19453293, ECO:0000269|PubMed:21667063}.
CC -!- INTERACTION:
CC O00244; P35670: ATP7B; NbExp=3; IntAct=EBI-10179267, EBI-11668501;
CC O00244; O43822: CFAP410; NbExp=3; IntAct=EBI-10179267, EBI-2835332;
CC O00244; P49747: COMP; NbExp=3; IntAct=EBI-10179267, EBI-2531022;
CC O00244; Q9NWS6: FAM118A; NbExp=6; IntAct=EBI-10179267, EBI-8638992;
CC O00244; O95749: GGPS1; NbExp=3; IntAct=EBI-10179267, EBI-10179283;
CC O00244; Q8N987: NECAB1; NbExp=3; IntAct=EBI-10179267, EBI-11956853;
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- DOMAIN: The heavy-metal-associated domain (HMA) coordinates a Cu(+) ion
CC via the cysteine residues within the CXXC motif. The transfer of Cu(+)
CC ion from ATOX1 to ATP7A involves the formation of a three-coordinate
CC Cu(+)-bridged heterodimer where the metal is shared between the two
CC metal binding sites of ATOX1 and ATP7A. The Cu(+) ion appears to switch
CC between two coordination modes, forming two links with one protein and
CC one with the other. Cisplatin, a chemotherapeutic drug, can bind the
CC CXXC motif and hinder the release of Cu(+) ion.
CC {ECO:0000269|PubMed:19453293, ECO:0000269|PubMed:31283225}.
CC -!- SIMILARITY: Belongs to the ATX1 family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/atox1/";
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DR EMBL; U70660; AAC51227.1; -; mRNA.
DR EMBL; AY165037; AAN84554.1; -; Genomic_DNA.
DR EMBL; BT009786; AAP88788.1; -; mRNA.
DR EMBL; AK293063; BAF85752.1; -; mRNA.
DR EMBL; AY986502; AAX81411.1; -; Genomic_DNA.
DR EMBL; CH471062; EAW61663.1; -; Genomic_DNA.
DR EMBL; CH471062; EAW61664.1; -; Genomic_DNA.
DR EMBL; BC112248; AAI12249.1; -; mRNA.
DR EMBL; BC112250; AAI12251.1; -; mRNA.
DR CCDS; CCDS47317.1; -.
DR RefSeq; NP_004036.1; NM_004045.3.
DR PDB; 1FE0; X-ray; 1.75 A; A/B=1-68.
DR PDB; 1FE4; X-ray; 1.75 A; A/B=1-68.
DR PDB; 1FEE; X-ray; 1.80 A; A/B=1-68.
DR PDB; 1TL4; NMR; -; A=1-68.
DR PDB; 1TL5; NMR; -; A=1-68.
DR PDB; 2K1R; NMR; -; B=1-68.
DR PDB; 2LQ9; NMR; -; A=1-68.
DR PDB; 3CJK; X-ray; 1.80 A; A=2-68.
DR PDB; 3IWL; X-ray; 1.60 A; A=1-68.
DR PDB; 3IWX; X-ray; 2.14 A; A/B=1-68.
DR PDB; 4QOT; X-ray; 2.20 A; A/B=1-68.
DR PDB; 4YDX; X-ray; 1.60 A; A=2-68.
DR PDB; 4YEA; X-ray; 2.14 A; A/B=2-68.
DR PDB; 5F0W; X-ray; 2.70 A; A/B/C/D=1-68.
DR PDB; 5T7L; X-ray; 2.83 A; A=2-68.
DR PDB; 7DC1; X-ray; 1.75 A; A/B=1-68.
DR PDB; 7ZC3; X-ray; 1.90 A; A/B=1-68.
DR PDBsum; 1FE0; -.
DR PDBsum; 1FE4; -.
DR PDBsum; 1FEE; -.
DR PDBsum; 1TL4; -.
DR PDBsum; 1TL5; -.
DR PDBsum; 2K1R; -.
DR PDBsum; 2LQ9; -.
DR PDBsum; 3CJK; -.
DR PDBsum; 3IWL; -.
DR PDBsum; 3IWX; -.
DR PDBsum; 4QOT; -.
DR PDBsum; 4YDX; -.
DR PDBsum; 4YEA; -.
DR PDBsum; 5F0W; -.
DR PDBsum; 5T7L; -.
DR PDBsum; 7DC1; -.
DR PDBsum; 7ZC3; -.
DR AlphaFoldDB; O00244; -.
DR BMRB; O00244; -.
DR SMR; O00244; -.
DR BioGRID; 106965; 22.
DR IntAct; O00244; 9.
DR STRING; 9606.ENSP00000430598; -.
DR DrugBank; DB03127; Benzamidine.
DR DrugBank; DB00515; Cisplatin.
DR DrugBank; DB09130; Copper.
DR DrugBank; DB02772; Sucrose.
DR GlyGen; O00244; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; O00244; -.
DR PhosphoSitePlus; O00244; -.
DR BioMuta; ATOX1; -.
DR EPD; O00244; -.
DR jPOST; O00244; -.
DR MassIVE; O00244; -.
DR MaxQB; O00244; -.
DR PaxDb; O00244; -.
DR PeptideAtlas; O00244; -.
DR PRIDE; O00244; -.
DR ProteomicsDB; 47805; -.
DR TopDownProteomics; O00244; -.
DR Antibodypedia; 28244; 231 antibodies from 24 providers.
DR DNASU; 475; -.
DR Ensembl; ENST00000313115.11; ENSP00000316854.6; ENSG00000177556.12.
DR Ensembl; ENST00000522710.1; ENSP00000429814.1; ENSG00000177556.12.
DR Ensembl; ENST00000524142.5; ENSP00000430598.1; ENSG00000177556.12.
DR GeneID; 475; -.
DR KEGG; hsa:475; -.
DR MANE-Select; ENST00000313115.11; ENSP00000316854.6; NM_004045.4; NP_004036.1.
DR UCSC; uc003luk.4; human.
DR CTD; 475; -.
DR DisGeNET; 475; -.
DR GeneCards; ATOX1; -.
DR HGNC; HGNC:798; ATOX1.
DR HPA; ENSG00000177556; Low tissue specificity.
DR MIM; 602270; gene.
DR neXtProt; NX_O00244; -.
DR OpenTargets; ENSG00000177556; -.
DR PharmGKB; PA25096; -.
DR VEuPathDB; HostDB:ENSG00000177556; -.
DR eggNOG; KOG1603; Eukaryota.
DR GeneTree; ENSGT00940000162517; -.
DR InParanoid; O00244; -.
DR OMA; MTHTYKF; -.
DR OrthoDB; 1564517at2759; -.
DR PhylomeDB; O00244; -.
DR TreeFam; TF352589; -.
DR PathwayCommons; O00244; -.
DR Reactome; R-HSA-3299685; Detoxification of Reactive Oxygen Species.
DR Reactome; R-HSA-6803544; Ion influx/efflux at host-pathogen interface.
DR SignaLink; O00244; -.
DR BioGRID-ORCS; 475; 21 hits in 1081 CRISPR screens.
DR ChiTaRS; ATOX1; human.
DR EvolutionaryTrace; O00244; -.
DR GeneWiki; ATOX1; -.
DR GenomeRNAi; 475; -.
DR Pharos; O00244; Tbio.
DR PRO; PR:O00244; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; O00244; protein.
DR Bgee; ENSG00000177556; Expressed in C1 segment of cervical spinal cord and 202 other tissues.
DR ExpressionAtlas; O00244; baseline and differential.
DR Genevisible; O00244; HS.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0016531; F:copper chaperone activity; IDA:UniProtKB.
DR GO; GO:0005507; F:copper ion binding; IDA:UniProtKB.
DR GO; GO:0032767; F:copper-dependent protein binding; IDA:UniProtKB.
DR GO; GO:1903136; F:cuprous ion binding; IDA:UniProtKB.
DR GO; GO:0016530; F:metallochaperone activity; TAS:UniProtKB.
DR GO; GO:0006878; P:cellular copper ion homeostasis; TAS:ProtInc.
DR GO; GO:0006825; P:copper ion transport; IBA:GO_Central.
DR GO; GO:0006979; P:response to oxidative stress; TAS:ProtInc.
DR CDD; cd00371; HMA; 1.
DR InterPro; IPR017969; Heavy-metal-associated_CS.
DR InterPro; IPR006121; HMA_dom.
DR InterPro; IPR036163; HMA_dom_sf.
DR Pfam; PF00403; HMA; 1.
DR SUPFAM; SSF55008; SSF55008; 1.
DR PROSITE; PS01047; HMA_1; 1.
DR PROSITE; PS50846; HMA_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Chaperone; Copper; Copper transport;
KW Ion transport; Metal-binding; Phosphoprotein; Reference proteome;
KW Transport.
FT CHAIN 1..68
FT /note="Copper transport protein ATOX1"
FT /id="PRO_0000212537"
FT DOMAIN 1..63
FT /note="HMA"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280"
FT BINDING 12
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280,
FT ECO:0000269|PubMed:31283225, ECO:0007744|PDB:5T7L"
FT BINDING 15
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280,
FT ECO:0000269|PubMed:31283225, ECO:0007744|PDB:5T7L"
FT MOD_RES 47
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 60
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:O08997"
FT MUTAGEN 15
FT /note="C->A: Impairs Cu(+)-bridged heterodimer formation
FT with ATP7A."
FT /evidence="ECO:0000269|PubMed:31283225"
FT MUTAGEN 21
FT /note="R->E: Has no overall effect on Cu(+)-bridged
FT heterodimer formation with ATP7A."
FT /evidence="ECO:0000269|PubMed:19453293"
FT MUTAGEN 22
FT /note="V->A: Has no overall effect on Cu(+)-bridged
FT heterodimer formation with ATP7A."
FT /evidence="ECO:0000269|PubMed:19453293"
FT MUTAGEN 58
FT /note="T->A: Has no overall effect on Cu(+)-bridged
FT heterodimer formation with ATP7A."
FT /evidence="ECO:0000269|PubMed:19453293"
FT STRAND 3..8
FT /evidence="ECO:0007829|PDB:3IWL"
FT HELIX 13..26
FT /evidence="ECO:0007829|PDB:3IWL"
FT STRAND 28..34
FT /evidence="ECO:0007829|PDB:3IWL"
FT TURN 35..38
FT /evidence="ECO:0007829|PDB:3IWL"
FT STRAND 39..46
FT /evidence="ECO:0007829|PDB:3IWL"
FT HELIX 48..56
FT /evidence="ECO:0007829|PDB:3IWL"
FT TURN 57..59
FT /evidence="ECO:0007829|PDB:1FE0"
FT STRAND 62..66
FT /evidence="ECO:0007829|PDB:3IWL"
SQ SEQUENCE 68 AA; 7402 MW; 0B364B1BD1279314 CRC64;
MPKHEFSVDM TCGGCAEAVS RVLNKLGGVK YDIDLPNKKV CIESEHSMDT LLATLKKTGK
TVSYLGLE
