CCC2/YDR270W Summary Help

Standard Name CCC2
Systematic Name YDR270W
Feature Type ORF, Verified
Description Cu(+2)-transporting P-type ATPase; required for export of copper from the cytosol into an extracytosolic compartment; has similarity to human proteins involved in Menkes and Wilsons diseases; protein abundance increases in response to DNA replication stress; affects TBSV model (+)RNA virus replication by regulating copper metabolism (1, 2, 3, 4 and see Summary Paragraph)
Name Description Cross-Complements Ca(2+) phenotype of csg1 2
Chromosomal Location
ChrIV:1005675 to 1008689 | ORF Map | GBrowse
Gbrowse
Gene Ontology Annotations All CCC2 GO evidence and references
  View Computational GO annotations for CCC2
Molecular Function
Manually curated
Biological Process
Manually curated
Cellular Component
Manually curated
High-throughput
Mutant phenotypes All CCC2 Phenotype evidence and references
Classical genetics
null
Large-scale survey
null
Resources
interactions All CCC2 Interaction evidence and references
39 total interaction(s) for 23 unique genes/features.
Physical Interactions
  • Affinity Capture-MS: 2
  • Affinity Capture-RNA: 1
  • Reconstituted Complex: 2
  • Two-hybrid: 4
Genetic Interactions
  • Dosage Lethality: 1
  • Dosage Rescue: 3
  • Negative Genetic: 13
  • Phenotypic Suppression: 1
  • Positive Genetic: 5
  • Synthetic Growth Defect: 6
  • Synthetic Lethality: 1
Resources
Expression Summary
histogram
Resources
Protein Information All CCC2 Protein evidence and references
Localization
Phosphorylation PhosphoGRID | PhosphoPep Database
Structure
Homologs
sequence information
ChrIV:1005675 to 1008689 | ORF Map | GBrowse
SGD ORF map
Last Update Coordinates: 2011-02-03 | Sequence: 1996-07-31
Subfeature details
Relative
Coordinates		 Chromosomal
Coordinates		 Most Recent Updates
Coordinates Sequence
CDS 1..3015 1005675..1008689 2011-02-03 1996-07-31
Retrieve sequences
Analyze Sequence
S288C only
S288C vs. other species
S288C vs. other strains
Resources
External Links All Associated Seq | E.C. | Entrez Gene | Entrez RefSeq Protein | MIPS | Search all NCBI (Entrez) | UniProtKB
Primary SGDIDS000002678
SUMMARY PARAGRAPH for CCC2

CCC2 encodes a P-type copper-transporting ATPase (EC 3.6.3.4) necessary for the proper uptake of iron (2). Ccc2p receives copper(I) ions (5) from Atx1p (6) and transports them into a late or post-Golgi compartment where they are acquired by the cell-surface iron transporter Fet3p (1, 7, 8, 9, 10), although there is also an Atx1p-independent pathway (7, 11, 12). CCC2 expression is regulated by iron and AFT1 (13).

CCC2 was originally identified as a gene whose twofold overexpression suppresses the calcium-sensitive growth phenotype of sur1 mutants (csg1 cross-complementing) (2). Deletion of CCC2 is not lethal (2) but causes several deficiencies that can be overcome by supplementing the growth medium with copper or, in some cases, iron. Among these are: defective iron uptake (7), slow growth on ethanol (indicating a defect in respiration) (1), and slow growth at neutral or alkaline pH (10, 11). ccc2 null mutants are deficient at making inositolphosphorylceramide D (IPC-D), possibly due to failure to deliver copper to an unknown enzyme (14).

Ccc2p is homologous to two human genes, called ATP7A (which is X-linked) (OMIM) and ATP7B (OMIM) (2). Mutations in ATP7A have been shown to cause Menkes disease (OMIM) and Occipital Horn Syndrome (OMIM). Mutations in ATP7B have been shown to cause Wilson disease (OMIM). Both ATP7A (15, 16) and ATP7B (17, 18, 19, 20) can complement deletion of CCC2 in yeast, as can Candida albicans CCC2 (21) and CCC2 homologs from C. elegans (22, 23), Arabidopsis thaliana (24), Trametes versicolor (25), and Brassica napus (26). An interesting splice variant of ATP7B that partially complements deletion of CCC2 is found in rats, lacks the copper-binding and transmembrane domains, and is expressed in the pineal gland at night (27).

Last updated: 2005-07-20

References cited on this page View Complete Literature Guide for CCC2
1) Yuan DS, et al.  (1995) The Menkes/Wilson disease gene homologue in yeast provides copper to a ceruloplasmin-like oxidase required for iron uptake. Proc Natl Acad Sci U S A 92(7):2632-6
2) Fu D, et al.  (1995) Sequence, mapping and disruption of CCC2, a gene that cross-complements the Ca(2+)-sensitive phenotype of csg1 mutants and encodes a P-type ATPase belonging to the Cu(2+)-ATPase subfamily. Yeast 11(3):283-92
3) Tkach JM, et al.  (2012) Dissecting DNA damage response pathways by analysing protein localization and abundance changes during DNA replication stress. Nat Cell Biol 14(9):966-76
4) Sasvari Z, et al.  (2013) The GEF1 proton-chloride exchanger affects tombusvirus replication via regulation of copper metabolism in yeast. J Virol 87(3):1800-10
5) Banci L, et al.  (2001) Solution structure of the yeast copper transporter domain Ccc2a in the apo and Cu(I)-loaded states. J Biol Chem 276(11):8415-26
6) Huffman DL and O'Halloran TV  (2000) Energetics of copper trafficking between the Atx1 metallochaperone and the intracellular copper transporter, Ccc2. J Biol Chem 275(25):18611-4
7) Lin SJ, et al.  (1997) A role for the Saccharomyces cerevisiae ATX1 gene in copper trafficking and iron transport. J Biol Chem 272(14):9215-20
8) Yuan DS, et al.  (1997) Restriction of copper export in Saccharomyces cerevisiae to a late Golgi or post-Golgi compartment in the secretory pathway. J Biol Chem 272(41):25787-93
9) Pufahl RA, et al.  (1997) Metal ion chaperone function of the soluble Cu(I) receptor Atx1. Science 278(5339):853-6
10) Gaxiola RA, et al.  (1998) The yeast CLC chloride channel functions in cation homeostasis. Proc Natl Acad Sci U S A 95(7):4046-50
11) Serrano R, et al.  (2004) Copper and iron are the limiting factors for growth of the yeast Saccharomyces cerevisiae in an alkaline environment. J Biol Chem 279(19):19698-704
12) Xiao Z, et al.  (2004) C-terminal domain of the membrane copper transporter Ctr1 from Saccharomyces cerevisiae binds four Cu(I) ions as a cuprous-thiolate polynuclear cluster: sub-femtomolar Cu(I) affinity of three proteins involved in copper trafficking. J Am Chem Soc 126(10):3081-90
13) Yamaguchi-Iwai Y, et al.  (1996) Iron-regulated DNA binding by the AFT1 protein controls the iron regulon in yeast. EMBO J 15(13):3377-84
14) Beeler TJ, et al.  (1997) SUR1 (CSG1/BCL21), a gene necessary for growth of Saccharomyces cerevisiae in the presence of high Ca2+ concentrations at 37 degrees C, is required for mannosylation of inositolphosphorylceramide. Mol Gen Genet 255(6):570-9
15) Payne AS and Gitlin JD  (1998) Functional expression of the menkes disease protein reveals common biochemical mechanisms among the copper-transporting P-type ATPases. J Biol Chem 273(6):3765-70
16) Mercer JF, et al.  (2003) Copper-induced trafficking of the cU-ATPases: a key mechanism for copper homeostasis. Biometals 16(1):175-84
17) Hung IH, et al.  (1997) Biochemical characterization of the Wilson disease protein and functional expression in the yeast Saccharomyces cerevisiae. J Biol Chem 272(34):21461-6
18) Iida M, et al.  (1998) Analysis of functional domains of Wilson disease protein (ATP7B) in Saccharomyces cerevisiae. FEBS Lett 428(3):281-5
19) Forbes JR and Cox DW  (1998) Functional characterization of missense mutations in ATP7B: Wilson disease mutation or normal variant? Am J Hum Genet 63(6):1663-74
20) Hsi G, et al.  (2004) Functional assessment of the carboxy-terminus of the Wilson disease copper-transporting ATPase, ATP7B. Genomics 83(3):473-81
21) Weissman Z, et al.  (2002) Deletion of the copper transporter CaCCC2 reveals two distinct pathways for iron acquisition in Candida albicans. Mol Microbiol 44(6):1551-60
22) Sambongi Y, et al.  (1997) Caenorhabditis elegans cDNA for a Menkes/Wilson disease gene homologue and its function in a yeast CCC2 gene deletion mutant. J Biochem 121(6):1169-75
23) Yoshimizu T, et al.  (1998) Essential Cys-Pro-Cys motif of Caenorhabditis elegans copper transport ATPase. Biosci Biotechnol Biochem 62(6):1258-60
24) Hirayama T, et al.  (1999) RESPONSIVE-TO-ANTAGONIST1, a Menkes/Wilson disease-related copper transporter, is required for ethylene signaling in Arabidopsis. Cell 97(3):383-93
25) Uldschmid A, et al.  (2003) Identification and functional expression of ctaA, a P-type ATPase gene involved in copper trafficking in Trametes versicolor. Microbiology 149(Pt 8):2039-48
26) Southron JL, et al.  (2004) Complementation of Saccharomyces cerevisiae ccc2 mutant by a putative P1B-ATPase from Brassica napus supports a copper-transporting function. FEBS Lett 566(1-3):218-22
27) Borjigin J, et al.  (1999) A novel pineal night-specific ATPase encoded by the Wilson disease gene. J Neurosci 19(3):1018-26