ID   CCC1_YEAST              Reviewed;         322 AA.
AC   P47818; D6VYM0;
DT   01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT   01-FEB-1996, sequence version 1.
DT   27-MAR-2024, entry version 176.
DE   RecName: Full=Protein CCC1;
DE   AltName: Full=Cross-complementer of CSG1 protein 1;
GN   Name=CCC1; OrderedLocusNames=YLR220W; ORFNames=L8083.6;
OS   Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Saccharomycotina; Saccharomycetes;
OC   Saccharomycetales; Saccharomycetaceae; Saccharomyces.
OX   NCBI_TaxID=559292;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=7941738; DOI=10.1002/yea.320100411;
RA   Fu D., Beeler T.J., Dunn T.M.;
RT   "Sequence, mapping and disruption of CCC1, a gene that cross-complements
RT   the Ca(2+)-sensitive phenotype of csg1 mutants.";
RL   Yeast 10:515-521(1994).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=ATCC 204508 / S288c;
RX   PubMed=9169871;
RA   Johnston M., Hillier L.W., Riles L., Albermann K., Andre B., Ansorge W.,
RA   Benes V., Brueckner M., Delius H., Dubois E., Duesterhoeft A.,
RA   Entian K.-D., Floeth M., Goffeau A., Hebling U., Heumann K.,
RA   Heuss-Neitzel D., Hilbert H., Hilger F., Kleine K., Koetter P., Louis E.J.,
RA   Messenguy F., Mewes H.-W., Miosga T., Moestl D., Mueller-Auer S.,
RA   Nentwich U., Obermaier B., Piravandi E., Pohl T.M., Portetelle D.,
RA   Purnelle B., Rechmann S., Rieger M., Rinke M., Rose M., Scharfe M.,
RA   Scherens B., Scholler P., Schwager C., Schwarz S., Underwood A.P.,
RA   Urrestarazu L.A., Vandenbol M., Verhasselt P., Vierendeels F., Voet M.,
RA   Volckaert G., Voss H., Wambutt R., Wedler E., Wedler H., Zimmermann F.K.,
RA   Zollner A., Hani J., Hoheisel J.D.;
RT   "The nucleotide sequence of Saccharomyces cerevisiae chromosome XII.";
RL   Nature 387:87-90(1997).
RN   [3]
RP   GENOME REANNOTATION.
RC   STRAIN=ATCC 204508 / S288c;
RX   PubMed=24374639; DOI=10.1534/g3.113.008995;
RA   Engel S.R., Dietrich F.S., Fisk D.G., Binkley G., Balakrishnan R.,
RA   Costanzo M.C., Dwight S.S., Hitz B.C., Karra K., Nash R.S., Weng S.,
RA   Wong E.D., Lloyd P., Skrzypek M.S., Miyasato S.R., Simison M., Cherry J.M.;
RT   "The reference genome sequence of Saccharomyces cerevisiae: Then and now.";
RL   G3 (Bethesda) 4:389-398(2014).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC   STRAIN=ATCC 204508 / S288c;
RX   PubMed=17322287; DOI=10.1101/gr.6037607;
RA   Hu Y., Rolfs A., Bhullar B., Murthy T.V.S., Zhu C., Berger M.F.,
RA   Camargo A.A., Kelley F., McCarron S., Jepson D., Richardson A., Raphael J.,
RA   Moreira D., Taycher E., Zuo D., Mohr S., Kane M.F., Williamson J.,
RA   Simpson A.J.G., Bulyk M.L., Harlow E., Marsischky G., Kolodner R.D.,
RA   LaBaer J.;
RT   "Approaching a complete repository of sequence-verified protein-encoding
RT   clones for Saccharomyces cerevisiae.";
RL   Genome Res. 17:536-543(2007).
RN   [5]
RP   FUNCTION.
RC   STRAIN=S288c / YPH1;
RX   PubMed=8668190; DOI=10.1128/mcb.16.7.3730;
RA   Pozos T.C., Sekler I., Cyert M.S.;
RT   "The product of HUM1, a novel yeast gene, is required for vacuolar Ca2+/H+
RT   exchange and is related to mammalian Na+/Ca2+ exchangers.";
RL   Mol. Cell. Biol. 16:3730-3741(1996).
RN   [6]
RP   FUNCTION, SUBCELLULAR LOCATION, AND DISRUPTION PHENOTYPE.
RX   PubMed=8866476; DOI=10.1111/j.1365-2958.1996.tb02561.x;
RA   Lapinskas P.J., Lin S.-J., Culotta V.C.;
RT   "The role of the Saccharomyces cerevisiae CCC1 gene in the homeostasis of
RT   manganese ions.";
RL   Mol. Microbiol. 21:519-528(1996).
RN   [7]
RP   OVEREXPRESSION PHENOTYPE.
RX   PubMed=10713071; DOI=10.1074/jbc.275.11.7626;
RA   Chen O.S., Kaplan J.;
RT   "CCC1 suppresses mitochondrial damage in the yeast model of Friedreich's
RT   ataxia by limiting mitochondrial iron accumulation.";
RL   J. Biol. Chem. 275:7626-7632(2000).
RN   [8]
RP   FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, AND CHARACTERIZATION
RP   OF DELETION MUTANT.
RX   PubMed=11390404; DOI=10.1074/jbc.m103944200;
RA   Li L., Chen O.S., McVey Ward D., Kaplan J.;
RT   "CCC1 is a transporter that mediates vacuolar iron storage in yeast.";
RL   J. Biol. Chem. 276:29515-29519(2001).
RN   [9]
RP   SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS].
RX   PubMed=14562095; DOI=10.1038/nature02026;
RA   Huh W.-K., Falvo J.V., Gerke L.C., Carroll A.S., Howson R.W.,
RA   Weissman J.S., O'Shea E.K.;
RT   "Global analysis of protein localization in budding yeast.";
RL   Nature 425:686-691(2003).
RN   [10]
RP   LEVEL OF PROTEIN EXPRESSION [LARGE SCALE ANALYSIS].
RX   PubMed=14562106; DOI=10.1038/nature02046;
RA   Ghaemmaghami S., Huh W.-K., Bower K., Howson R.W., Belle A., Dephoure N.,
RA   O'Shea E.K., Weissman J.S.;
RT   "Global analysis of protein expression in yeast.";
RL   Nature 425:737-741(2003).
RN   [11]
RP   CHARACTERIZATION OF DELETION MUTANT.
RX   PubMed=15161905; DOI=10.1074/jbc.m403146200;
RA   Li L., Kaplan J.;
RT   "A mitochondrial-vacuolar signaling pathway in yeast that affects iron and
RT   copper metabolism.";
RL   J. Biol. Chem. 279:33653-33661(2004).
RN   [12]
RP   INDUCTION.
RX   PubMed=15652485; DOI=10.1016/j.cell.2004.11.032;
RA   Puig S., Askeland E., Thiele D.J.;
RT   "Coordinated remodeling of cellular metabolism during iron deficiency
RT   through targeted mRNA degradation.";
RL   Cell 120:99-110(2005).
RN   [13]
RP   TOPOLOGY [LARGE SCALE ANALYSIS].
RC   STRAIN=ATCC 208353 / W303-1A;
RX   PubMed=16847258; DOI=10.1073/pnas.0604075103;
RA   Kim H., Melen K., Oesterberg M., von Heijne G.;
RT   "A global topology map of the Saccharomyces cerevisiae membrane proteome.";
RL   Proc. Natl. Acad. Sci. U.S.A. 103:11142-11147(2006).
RN   [14]
RP   EFFECT OF OVEREXPRESSION.
RX   PubMed=17603109; DOI=10.1534/genetics.107.073577;
RA   Devasahayam G., Burke D.J., Sturgill T.W.;
RT   "Golgi manganese transport is required for rapamycin signaling in
RT   Saccharomyces cerevisiae.";
RL   Genetics 177:231-238(2007).
RN   [15]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   STRAIN=ADR376;
RX   PubMed=17330950; DOI=10.1021/pr060559j;
RA   Li X., Gerber S.A., Rudner A.D., Beausoleil S.A., Haas W., Villen J.,
RA   Elias J.E., Gygi S.P.;
RT   "Large-scale phosphorylation analysis of alpha-factor-arrested
RT   Saccharomyces cerevisiae.";
RL   J. Proteome Res. 6:1190-1197(2007).
RN   [16]
RP   INDUCTION.
RX   PubMed=18070921; DOI=10.1128/mcb.01219-07;
RA   Li L., Bagley D., Ward D.M., Kaplan J.;
RT   "Yap5 is an iron-responsive transcriptional activator that regulates
RT   vacuolar iron storage in yeast.";
RL   Mol. Cell. Biol. 28:1326-1337(2008).
RN   [17]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-29; SER-68; SER-71 AND
RP   SER-83, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=18407956; DOI=10.1074/mcp.m700468-mcp200;
RA   Albuquerque C.P., Smolka M.B., Payne S.H., Bafna V., Eng J., Zhou H.;
RT   "A multidimensional chromatography technology for in-depth phosphoproteome
RT   analysis.";
RL   Mol. Cell. Proteomics 7:1389-1396(2008).
RN   [18]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-53; SER-68; SER-71 AND
RP   SER-83, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19779198; DOI=10.1126/science.1172867;
RA   Holt L.J., Tuch B.B., Villen J., Johnson A.D., Gygi S.P., Morgan D.O.;
RT   "Global analysis of Cdk1 substrate phosphorylation sites provides insights
RT   into evolution.";
RL   Science 325:1682-1686(2009).
CC   -!- FUNCTION: Has a role in both calcium and manganese homeostasis.
CC       Involved in the transfer of iron and Mn(2+) from the cytosol to the
CC       vacuole for storage of these metals. {ECO:0000269|PubMed:11390404,
CC       ECO:0000269|PubMed:8668190, ECO:0000269|PubMed:8866476}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Fe(2+)(in) = Fe(2+)(out); Xref=Rhea:RHEA:28486,
CC         ChEBI:CHEBI:29033; Evidence={ECO:0000269|PubMed:11390404};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:28487;
CC         Evidence={ECO:0000305};
CC   -!- SUBCELLULAR LOCATION: Golgi apparatus membrane
CC       {ECO:0000269|PubMed:11390404, ECO:0000269|PubMed:14562095,
CC       ECO:0000269|PubMed:8866476}. Vacuole membrane {ECO:0000305}; Multi-pass
CC       membrane protein {ECO:0000305}.
CC   -!- INDUCTION: Down-regulated under iron starvation by TIS11.
CC       Transcriptionally up-regulated by YAP5 in response to increased
CC       cytosolic iron. {ECO:0000269|PubMed:15652485,
CC       ECO:0000269|PubMed:18070921}.
CC   -!- DISRUPTION PHENOTYPE: Deletion causes an increase in metal sensitivity
CC       at 15 mM manganese, but does not affect invertase glycosylation.
CC       Deletion shows increased sensitivity to external iron, which is
CC       suppressed by MRS3 or MRS4 overexpression requiring oxygen but not
CC       respiration, and exacerbated by ectopic expression of the iron
CC       transporter FET4. Deletion also results in decreased vacuolar iron
CC       content and decreased iron stores, which affect cytosolic iron levels
CC       and cell growth. Deletion together with MRS3 and MRS4 restores cellular
CC       and mitochondrial iron homeostasis to near normal level, corrects the
CC       MRS3 and MRS4 double deletion phenotype (which shows increased
CC       resistance to cobalt but decreased resistance to copper and cadmium),
CC       and has near normal levels of aconitase activity. When overexpressed,
CC       maintains respiratory function in a YFH1 deletion mutant regardless of
CC       extracellular iron concentration, activates the iron-dependent
CC       transcription factor AFT1 resulting in an increase in iron uptake,
CC       cytosolic iron accumulation and a change in copper metabolism.
CC       Overexpression prevents excessive mitochondrial iron accumulation by
CC       limiting mitochondrial iron uptake and results in increased expression
CC       of the high affinity iron transport system composed of FET3 and FTR1.
CC       Overexpression also suppresses the rapamycin-resistant phenotype of
CC       PMR1 deletion mutant. {ECO:0000269|PubMed:8866476}.
CC   -!- MISCELLANEOUS: Present with 2840 molecules/cell in log phase SD medium.
CC       {ECO:0000269|PubMed:14562106}.
CC   -!- SIMILARITY: Belongs to the CCC1 family. {ECO:0000305}.
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DR   EMBL; L24112; AAA62622.1; -; mRNA.
DR   EMBL; U14913; AAB67452.1; -; Genomic_DNA.
DR   EMBL; U19027; AAB67409.1; -; Genomic_DNA.
DR   EMBL; AY557952; AAS56278.1; -; Genomic_DNA.
DR   EMBL; BK006945; DAA09536.1; -; Genomic_DNA.
DR   PIR; S43453; S43453.
DR   RefSeq; NP_013321.1; NM_001182107.1.
DR   AlphaFoldDB; P47818; -.
DR   SMR; P47818; -.
DR   BioGRID; 31487; 134.
DR   DIP; DIP-782N; -.
DR   IntAct; P47818; 1.
DR   MINT; P47818; -.
DR   STRING; 4932.YLR220W; -.
DR   TCDB; 2.A.89.1.1; the vacuolar iron transporter (vit) family.
DR   iPTMnet; P47818; -.
DR   MaxQB; P47818; -.
DR   PaxDb; 4932-YLR220W; -.
DR   PeptideAtlas; P47818; -.
DR   EnsemblFungi; YLR220W_mRNA; YLR220W; YLR220W.
DR   GeneID; 850917; -.
DR   KEGG; sce:YLR220W; -.
DR   AGR; SGD:S000004210; -.
DR   SGD; S000004210; CCC1.
DR   VEuPathDB; FungiDB:YLR220W; -.
DR   eggNOG; KOG4473; Eukaryota.
DR   HOGENOM; CLU_038957_0_0_1; -.
DR   InParanoid; P47818; -.
DR   OMA; MNFHHTL; -.
DR   OrthoDB; 1357at2759; -.
DR   BioCyc; YEAST:G3O-32334-MONOMER; -.
DR   BioGRID-ORCS; 850917; 3 hits in 10 CRISPR screens.
DR   PRO; PR:P47818; -.
DR   Proteomes; UP000002311; Chromosome XII.
DR   RNAct; P47818; Protein.
DR   GO; GO:0000324; C:fungal-type vacuole; IDA:SGD.
DR   GO; GO:0000329; C:fungal-type vacuole membrane; IDA:SGD.
DR   GO; GO:0005794; C:Golgi apparatus; IDA:SGD.
DR   GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0015093; F:ferrous iron transmembrane transporter activity; IMP:SGD.
DR   GO; GO:0005381; F:iron ion transmembrane transporter activity; IBA:GO_Central.
DR   GO; GO:0005384; F:manganese ion transmembrane transporter activity; IMP:SGD.
DR   GO; GO:0006874; P:intracellular calcium ion homeostasis; IMP:SGD.
DR   GO; GO:0006879; P:intracellular iron ion homeostasis; IMP:SGD.
DR   GO; GO:0030026; P:intracellular manganese ion homeostasis; IMP:SGD.
DR   GO; GO:0006880; P:intracellular sequestering of iron ion; IBA:GO_Central.
DR   GO; GO:0006826; P:iron ion transport; IMP:SGD.
DR   GO; GO:0006828; P:manganese ion transport; IMP:SGD.
DR   CDD; cd02435; CCC1; 1.
DR   InterPro; IPR008217; Ccc1_fam.
DR   PANTHER; PTHR31851; FE(2+)/MN(2+) TRANSPORTER PCL1; 1.
DR   PANTHER; PTHR31851:SF52; PROTEIN CCC1; 1.
DR   Pfam; PF01988; VIT1; 1.
PE   1: Evidence at protein level;
KW   Golgi apparatus; Membrane; Phosphoprotein; Reference proteome;
KW   Transmembrane; Transmembrane helix; Transport; Vacuole.
FT   CHAIN           1..322
FT                   /note="Protein CCC1"
FT                   /id="PRO_0000089394"
FT   TOPO_DOM        1..99
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        100..120
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        121..129
FT                   /note="Vacuolar"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        130..150
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        151..236
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        237..257
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        258..259
FT                   /note="Vacuolar"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        260..280
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        281..300
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        301..321
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        322
FT                   /note="Vacuolar"
FT                   /evidence="ECO:0000255"
FT   REGION          19..86
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOD_RES         29
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18407956"
FT   MOD_RES         53
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:19779198"
FT   MOD_RES         68
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18407956,
FT                   ECO:0007744|PubMed:19779198"
FT   MOD_RES         71
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18407956,
FT                   ECO:0007744|PubMed:19779198"
FT   MOD_RES         83
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:17330950,
FT                   ECO:0007744|PubMed:18407956, ECO:0007744|PubMed:19779198"
SQ   SEQUENCE   322 AA;  34250 MW;  374081A49F0C43D1 CRC64;
     MSIVALKNAV VTLIQKAKGS GGTSELGGSE STPLLRGSNS NSSRHDNLSS SSSDIIYGRN
     SAQDLENSPM SVGKDNRNGD NGSDNEKANL GFFQSVDPRV ISDLIIGLSD GLTVPFALTA
     GLSSLGDAKL VITGGFAELI SGAISMGLGG YLGAKSESDY YHAEVKKEKR KFYDNSNLIN
     REIEDILLEI NPNFSDETIV SFIKDLQRTP ELMVDFIIRY GRGLDEPAEN RELISAVTIG
     GGYLLGGLVP LVPYFFVSDV GTGLIYSIIV MVVTLFWFGY VKTKLSMGSG SSTSKKVTEG
     VEMVVVGGVA AGAAWFFVKL LG
//