CCS_HUMAN
ID CCS_HUMAN Reviewed; 274 AA.
AC O14618; Q2M366; Q8NEV0;
DT 31-JAN-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1998, sequence version 1.
DT 03-AUG-2022, entry version 198.
DE RecName: Full=Copper chaperone for superoxide dismutase;
DE AltName: Full=Superoxide dismutase copper chaperone;
GN Name=CCS;
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].
RX PubMed=9295278; DOI=10.1074/jbc.272.38.23469;
RA Culotta V.C., Klomp L.W., Strain J., Casareno R.L.B., Krems B.,
RA Gitlin J.D.;
RT "The copper chaperone for superoxide dismutase.";
RL J. Biol. Chem. 272:23469-23472(1997).
RN [2]
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 [3]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-267, AND IDENTIFICATION BY
RP 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 [4]
RP STRUCTURE BY NMR OF 1-85, COPPER-BINDING SITES, AND SUBUNIT.
RX PubMed=23625804; DOI=10.1002/cbic.201300042;
RA Banci L., Cantini F., Kozyreva T., Rubino J.T.;
RT "Mechanistic aspects of hSOD1 maturation from the solution structure of
RT Cu(I) -loaded hCCS domain 1 and analysis of disulfide-free hSOD1 mutants.";
RL ChemBioChem 14:1839-1844(2013).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Bhat K.S.;
RT "Human macrophage copper chaperone for superoxide dismutase (CCS), full
RT length mRNA sequence.";
RL Submitted (MAY-2002) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S., Neubert P.,
RA Kstrang K., Schatten R., Shen B., Henze S., Mar W., Korn B., Zuo D., Hu Y.,
RA LaBaer J.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 SUBUNIT, AND SUBCELLULAR LOCATION.
RX PubMed=9726962; DOI=10.1074/jbc.273.37.23625;
RA Casareno R.L.B., Waggoner D., Gitlin J.D.;
RT "The copper chaperone CCS directly interacts with copper/zinc superoxide
RT dismutase.";
RL J. Biol. Chem. 273:23625-23628(1998).
RN [9]
RP MUTAGENESIS OF CYS-22; CYS-25; CYS-244 AND CYS-246, AND METAL-BINDING.
RX PubMed=15736924; DOI=10.1021/bi0478392;
RA Stasser J.P., Eisses J.F., Barry A.N., Kaplan J.H., Blackburn N.J.;
RT "Cysteine-to-serine mutants of the human copper chaperone for superoxide
RT dismutase reveal a copper cluster at a domain III dimer interface.";
RL Biochemistry 44:3143-3152(2005).
RN [10]
RP INTERACTION WITH COMMD1.
RX PubMed=20595380; DOI=10.1074/jbc.m110.101477;
RA Vonk W.I., Wijmenga C., Berger R., van de Sluis B., Klomp L.W.;
RT "Cu,Zn superoxide dismutase maturation and activity are regulated by
RT COMMD1.";
RL J. Biol. Chem. 285:28991-29000(2010).
RN [11]
RP UBIQUITINATION AT LYS-76; LYS-189; LYS-216 AND LYS-241 BY XIAP/BIRC4, AND
RP INTERACTION WITH XIAP/BIRC4.
RX PubMed=20154138; DOI=10.1128/mcb.00900-09;
RA Brady G.F., Galban S., Liu X., Basrur V., Gitlin J.D.,
RA Elenitoba-Johnson K.S., Wilson T.E., Duckett C.S.;
RT "Regulation of the copper chaperone CCS by XIAP-mediated ubiquitination.";
RL Mol. Cell. Biol. 30:1923-1936(2010).
RN [12]
RP INTERACTION WITH SOD1, VARIANT TRP-163, AND CHARACTERIZATION OF VARIANT
RP TRP-163.
RX PubMed=22508683; DOI=10.1002/humu.22099;
RA Huppke P., Brendel C., Korenke G.C., Marquardt I., Donsante A., Yi L.,
RA Hicks J.D., Steinbach P.J., Wilson C., Elpeleg O., Moller L.B.,
RA Christodoulou J., Kaler S.G., Gartner J.;
RT "Molecular and biochemical characterization of a unique mutation in CCS,
RT the human copper chaperone to superoxide dismutase.";
RL Hum. Mutat. 33:1207-1215(2012).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (2.75 ANGSTROMS) OF 84-237 IN COMPLEX WITH ZINC,
RP SUBUNIT, AND DISULFIDE BOND.
RX PubMed=10677207; DOI=10.1021/bi992822i;
RA Lamb A.L., Wernimont A.K., Pufahl R.A., O'Halloran T.V., Rosenzweig A.C.;
RT "Crystal structure of the second domain of the human copper chaperone for
RT superoxide dismutase.";
RL Biochemistry 39:1589-1595(2000).
RN [14]
RP STRUCTURE BY NMR OF 1-87.
RG RIKEN structural genomics initiative (RSGI);
RT "The apo form of HMA domain of copper chaperone for superoxide dismutase.";
RL Submitted (NOV-2005) to the PDB data bank.
CC -!- FUNCTION: Delivers copper to copper zinc superoxide dismutase (SOD1).
CC -!- COFACTOR:
CC Name=Cu(2+); Xref=ChEBI:CHEBI:29036; Evidence={ECO:0007744|PDB:2RSQ};
CC Note=Binds 2 copper ions per subunit. {ECO:0007744|PDB:2RSQ};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000269|PubMed:10677207};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000269|PubMed:10677207};
CC -!- SUBUNIT: Homodimer, and heterodimer with SOD1. Interacts with COMMD1.
CC Interacts with XIAP/BIRC4. {ECO:0000269|PubMed:10677207,
CC ECO:0000269|PubMed:20154138, ECO:0000269|PubMed:20595380,
CC ECO:0000269|PubMed:22508683, ECO:0000269|PubMed:23625804,
CC ECO:0000269|PubMed:9726962}.
CC -!- INTERACTION:
CC O14618; Q9NWV4: CZIB; NbExp=3; IntAct=EBI-11668690, EBI-724109;
CC O14618; P00441: SOD1; NbExp=4; IntAct=EBI-11668690, EBI-990792;
CC O14618; P98170: XIAP; NbExp=2; IntAct=EBI-11668690, EBI-517127;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:9726962}.
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- PTM: Ubiquitinion by XIAP/BIRC4 leads to enhancement of its chaperone
CC activity toward its physiologic target, SOD1, rather than proteasomal
CC degradation. XIAP/BIRC4 preferentially ubiquitinates at Lys-241.
CC {ECO:0000269|PubMed:20154138}.
CC -!- SIMILARITY: In the C-terminal section; belongs to the Cu-Zn superoxide
CC dismutase family. {ECO:0000305}.
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DR EMBL; AF002210; AAC51764.1; -; mRNA.
DR EMBL; AY113179; AAM50090.1; -; mRNA.
DR EMBL; CR541928; CAG46726.1; -; mRNA.
DR EMBL; BC105016; AAI05017.1; -; mRNA.
DR EMBL; BC112055; AAI12056.1; -; mRNA.
DR CCDS; CCDS8146.1; -.
DR RefSeq; NP_005116.1; NM_005125.1.
DR PDB; 1DO5; X-ray; 2.75 A; A/B/C/D=84-237.
DR PDB; 2CRL; NMR; -; A=1-85.
DR PDB; 2RSQ; NMR; -; A=1-85.
DR PDB; 6FN8; X-ray; 1.55 A; A/B=85-236.
DR PDB; 6FOL; X-ray; 2.55 A; A/D/E/H=85-232.
DR PDB; 6FON; X-ray; 3.05 A; A/C=8-259.
DR PDB; 6FP6; X-ray; 3.00 A; B/D/F/H/J/L/N/P/R/T/V/X=1-274.
DR PDBsum; 1DO5; -.
DR PDBsum; 2CRL; -.
DR PDBsum; 2RSQ; -.
DR PDBsum; 6FN8; -.
DR PDBsum; 6FOL; -.
DR PDBsum; 6FON; -.
DR PDBsum; 6FP6; -.
DR AlphaFoldDB; O14618; -.
DR BMRB; O14618; -.
DR SMR; O14618; -.
DR BioGRID; 115298; 37.
DR IntAct; O14618; 8.
DR MINT; O14618; -.
DR STRING; 9606.ENSP00000436318; -.
DR DrugBank; DB09130; Copper.
DR DrugBank; DB01593; Zinc.
DR DrugBank; DB14487; Zinc acetate.
DR DrugBank; DB14533; Zinc chloride.
DR DrugBank; DB14548; Zinc sulfate, unspecified form.
DR GlyGen; O14618; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; O14618; -.
DR PhosphoSitePlus; O14618; -.
DR SwissPalm; O14618; -.
DR BioMuta; CCS; -.
DR OGP; O14618; -.
DR EPD; O14618; -.
DR jPOST; O14618; -.
DR MassIVE; O14618; -.
DR MaxQB; O14618; -.
DR PaxDb; O14618; -.
DR PeptideAtlas; O14618; -.
DR PRIDE; O14618; -.
DR ProteomicsDB; 48122; -.
DR Antibodypedia; 30210; 375 antibodies from 32 providers.
DR DNASU; 9973; -.
DR Ensembl; ENST00000533244.6; ENSP00000436318.1; ENSG00000173992.9.
DR GeneID; 9973; -.
DR KEGG; hsa:9973; -.
DR MANE-Select; ENST00000533244.6; ENSP00000436318.1; NM_005125.2; NP_005116.1.
DR UCSC; uc001oir.4; human.
DR CTD; 9973; -.
DR DisGeNET; 9973; -.
DR GeneCards; CCS; -.
DR HGNC; HGNC:1613; CCS.
DR HPA; ENSG00000173992; Low tissue specificity.
DR MIM; 603864; gene.
DR neXtProt; NX_O14618; -.
DR OpenTargets; ENSG00000173992; -.
DR PharmGKB; PA26177; -.
DR VEuPathDB; HostDB:ENSG00000173992; -.
DR eggNOG; KOG4656; Eukaryota.
DR GeneTree; ENSGT00940000159785; -.
DR InParanoid; O14618; -.
DR OMA; KGMGSDQ; -.
DR OrthoDB; 1527306at2759; -.
DR PhylomeDB; O14618; -.
DR TreeFam; TF105184; -.
DR PathwayCommons; O14618; -.
DR Reactome; R-HSA-3299685; Detoxification of Reactive Oxygen Species.
DR SignaLink; O14618; -.
DR BioGRID-ORCS; 9973; 69 hits in 1082 CRISPR screens.
DR EvolutionaryTrace; O14618; -.
DR GeneWiki; CCS_(gene); -.
DR GenomeRNAi; 9973; -.
DR Pharos; O14618; Tbio.
DR PRO; PR:O14618; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; O14618; protein.
DR Bgee; ENSG00000173992; Expressed in right lobe of liver and 191 other tissues.
DR ExpressionAtlas; O14618; baseline and differential.
DR Genevisible; O14618; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0045296; F:cadherin binding; HDA:BHF-UCL.
DR GO; GO:0005507; F:copper ion binding; IDA:GO_Central.
DR GO; GO:0015035; F:protein-disulfide reductase activity; TAS:Reactome.
DR GO; GO:0034599; P:cellular response to oxidative stress; TAS:Reactome.
DR GO; GO:0051353; P:positive regulation of oxidoreductase activity; IEA:Ensembl.
DR GO; GO:0015680; P:protein maturation by copper ion transfer; TAS:ProtInc.
DR GO; GO:0019430; P:removal of superoxide radicals; IBA:GO_Central.
DR GO; GO:0006801; P:superoxide metabolic process; TAS:ProtInc.
DR CDD; cd00305; Cu-Zn_Superoxide_Dismutase; 1.
DR CDD; cd00371; HMA; 1.
DR Gene3D; 2.60.40.200; -; 1.
DR InterPro; IPR006121; HMA_dom.
DR InterPro; IPR036163; HMA_dom_sf.
DR InterPro; IPR036423; SOD-like_Cu/Zn_dom_sf.
DR InterPro; IPR024134; SOD_Cu/Zn_/chaperone.
DR InterPro; IPR018152; SOD_Cu/Zn_BS.
DR InterPro; IPR001424; SOD_Cu_Zn_dom.
DR PANTHER; PTHR10003; PTHR10003; 1.
DR Pfam; PF00403; HMA; 1.
DR Pfam; PF00080; Sod_Cu; 1.
DR PRINTS; PR00068; CUZNDISMTASE.
DR SUPFAM; SSF49329; SSF49329; 1.
DR SUPFAM; SSF55008; SSF55008; 1.
DR PROSITE; PS50846; HMA_2; 1.
DR PROSITE; PS00332; SOD_CU_ZN_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Chaperone; Copper; Cytoplasm; Disulfide bond;
KW Isopeptide bond; Metal-binding; Phosphoprotein; Reference proteome;
KW Ubl conjugation; Zinc.
FT CHAIN 1..274
FT /note="Copper chaperone for superoxide dismutase"
FT /id="PRO_0000213543"
FT DOMAIN 11..74
FT /note="HMA"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280"
FT REGION 88..234
FT /note="Superoxide dismutase-like"
FT BINDING 22
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280,
FT ECO:0007744|PDB:2RSQ"
FT BINDING 25
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00280,
FT ECO:0007744|PDB:2RSQ"
FT BINDING 147
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:10677207,
FT ECO:0007744|PDB:1DO5"
FT BINDING 155
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:10677207,
FT ECO:0007744|PDB:1DO5"
FT BINDING 164
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:10677207,
FT ECO:0007744|PDB:1DO5"
FT BINDING 167
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:10677207,
FT ECO:0007744|PDB:1DO5"
FT BINDING 244
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="2"
FT BINDING 246
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="2"
FT MOD_RES 267
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT DISULFID 141..227
FT /evidence="ECO:0000269|PubMed:10677207,
FT ECO:0007744|PDB:1DO5"
FT CROSSLNK 76
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:20154138"
FT CROSSLNK 189
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:20154138"
FT CROSSLNK 216
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:20154138"
FT CROSSLNK 241
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:20154138"
FT VARIANT 163
FT /note="R -> W (found in a patient with congenital
FT cataracts, hearing loss, neurodegeneration, neonatal
FT hypotonia and hypoglycemia, pericardial effusion and
FT neurodevelopmental regression after infection; the patient
FT also carries a mutation in SLC33A1; mutant protein does not
FT interact with SOD1; dbSNP:rs142340643)"
FT /evidence="ECO:0000269|PubMed:22508683"
FT /id="VAR_068078"
FT MUTAGEN 22
FT /note="C->S: Reduces copper binding by half; when
FT associated with S-25. Negligible effect on zinc binding."
FT /evidence="ECO:0000269|PubMed:15736924"
FT MUTAGEN 25
FT /note="C->S: Reduces copper binding by half; when
FT associated with S-22. Negligible effect on zinc binding."
FT /evidence="ECO:0000269|PubMed:15736924"
FT MUTAGEN 244
FT /note="C->S: Reduces copper binding by half; when
FT associated with S-246. Negligible effect on zinc binding."
FT /evidence="ECO:0000269|PubMed:15736924"
FT MUTAGEN 246
FT /note="C->S: Reduces copper binding by half; when
FT associated with S-244. Negligible effect on zinc binding."
FT /evidence="ECO:0000269|PubMed:15736924"
FT CONFLICT 116
FT /note="E -> D (in Ref. 4; AAM50090)"
FT /evidence="ECO:0000305"
FT STRAND 12..18
FT /evidence="ECO:0007829|PDB:6FP6"
FT HELIX 23..33
FT /evidence="ECO:0007829|PDB:6FP6"
FT STRAND 39..45
FT /evidence="ECO:0007829|PDB:6FP6"
FT TURN 46..49
FT /evidence="ECO:0007829|PDB:6FP6"
FT STRAND 50..57
FT /evidence="ECO:0007829|PDB:6FP6"
FT HELIX 59..67
FT /evidence="ECO:0007829|PDB:6FP6"
FT STRAND 69..71
FT /evidence="ECO:0007829|PDB:6FP6"
FT STRAND 73..80
FT /evidence="ECO:0007829|PDB:6FP6"
FT STRAND 88..94
FT /evidence="ECO:0007829|PDB:6FN8"
FT STRAND 96..98
FT /evidence="ECO:0007829|PDB:6FN8"
FT STRAND 100..109
FT /evidence="ECO:0007829|PDB:6FN8"
FT STRAND 112..121
FT /evidence="ECO:0007829|PDB:6FN8"
FT STRAND 124..133
FT /evidence="ECO:0007829|PDB:6FN8"
FT HELIX 140..144
FT /evidence="ECO:0007829|PDB:6FN8"
FT STRAND 160..163
FT /evidence="ECO:0007829|PDB:6FOL"
FT STRAND 167..173
FT /evidence="ECO:0007829|PDB:6FN8"
FT STRAND 179..187
FT /evidence="ECO:0007829|PDB:6FN8"
FT HELIX 190..193
FT /evidence="ECO:0007829|PDB:6FN8"
FT STRAND 196..203
FT /evidence="ECO:0007829|PDB:6FN8"
FT TURN 213..218
FT /evidence="ECO:0007829|PDB:6FN8"
FT STRAND 223..233
FT /evidence="ECO:0007829|PDB:6FN8"
FT STRAND 241..246
FT /evidence="ECO:0007829|PDB:6FON"
FT STRAND 249..253
FT /evidence="ECO:0007829|PDB:6FON"
SQ SEQUENCE 274 AA; 29041 MW; A392432954B65760 CRC64;
MASDSGNQGT LCTLEFAVQM TCQSCVDAVR KSLQGVAGVQ DVEVHLEDQM VLVHTTLPSQ
EVQALLEGTG RQAVLKGMGS GQLQNLGAAV AILGGPGTVQ GVVRFLQLTP ERCLIEGTID
GLEPGLHGLH VHQYGDLTNN CNSCGNHFNP DGASHGGPQD SDRHRGDLGN VRADADGRAI
FRMEDEQLKV WDVIGRSLII DEGEDDLGRG GHPLSKITGN SGERLACGII ARSAGLFQNP
KQICSCDGLT IWEERGRPIA GKGRKESAQP PAHL
