CCS (gene)

Copper chaperone for superoxide dismutase is a metalloprotein that is responsible for the delivery of Cu to superoxide dismutase (SOD1).[5] CCS is a 54kDa protein that is present in mammals and most eukaryotes including yeast. The structure of CCS is composed of three distinct domains that are necessary for its function.[6][7] Although CCS is important for many organisms, there are CCS independent pathways for SOD1, and many species lack CCS all together, such as C. elegans.[7] In humans the protein is encoded by the CCS gene.[8][9]

CCS
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCCS, copper chaperone for superoxide dismutase
External IDsOMIM: 603864 MGI: 1333783 HomoloGene: 3762 GeneCards: CCS
Gene location (Human)
Chr.Chromosome 11 (human)[1]
Band11q13.2Start66,593,153 bp[1]
End66,606,019 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

9973

12460

Ensembl

ENSG00000173992

ENSMUSG00000034108

UniProt

O14618

Q9WU84

RefSeq (mRNA)

NM_005125

NM_016892

RefSeq (protein)

NP_005116

NP_058588

Location (UCSC)Chr 11: 66.59 – 66.61 MbChr 19: 4.83 – 4.84 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure and function

CCS is composed of three domains.[5] Domain I is located on the N-terminus and contains the MXCXXC Cu binding sequence.[5] It has been determined to be necessary for function of CCS but its specific role is currently unknown.[5] The structure of domain II greatly resembles that of SOD1 which allows it to perform the function of binding to SOD1.[5] Domain III contains a CXC Cu binding motif and performs the Cu insertion and subsequent disulfide oxidation of SOD1.[5]

When CCS docks to SOD1, cysteine 244 of CCS and 57 of SOD1 form a disulfide linkage.[6] This disulfide bond is then transferred to form a disulfide bridge between cysteine 57 and 146 of SOD1.[6] CCS's catalytic oxidation of SOD1's disulfide bridge can only be performed in the presence of oxygen.[6] Furthermore, the disulfide linkage of SOD1 can be performed without the presence of CCS but requires oxygen and is much slower.[6] Additionally, CCS is proposed to help the proper folding of SOD1 by binding in the apo-state.[6]

As well as SOD1, CCS (gene) has been shown to interact with APBA1.[10]

Localization

CCS is localized in the nucleus, cytosol, and mitochondrial intermembrane space.[7] CCS is imported to the mitochondria by Mia40 and Erv1 disulfide relay system.[7] The cysteine 64 of CCS Domain I generates a disulfide intermediate with Mia40.[7] This disulfide bond is transferred to link cysteine 64 and 27 of CCS, stabilizing the protein in the mitochondrial intermembrane space where it delivers Cu to the Cu-less apo-SOD1.[6][7]

Role in copper homeostasis

In mammals cellular Cu levels are regulated by CCS's interaction with the 26S proteasome.[7] During times of Cu excess CCS delivers Cu to XIAP and primes the complex for auto-ubiquitination and subsequent degradation.[7] Expression of SOD1 is not modified by Cu availability but by CCS ability to deliver Cu.[7] Knockouts of CCS (Δccs) show 70-90% decrease in SOD1 activity as well as increased expression of Cu binding proteins, namely, MT-I, MT-II, ATOX1, COX17, ATP7A to, presumably, reduce the amount of free Cu.[7]

Cells with CCS mutants have been shown to display ALS like symptoms.[6] Moreover, SOD1 mutants that have altered interactions with CCS have been shown to display misfolding and aggregation.[6]

References
  1. GRCh38: Ensembl release 89: ENSG00000173992 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000034108 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Fukai T, Ushio-Fukai M (Sep 2011). "Superoxide dismutases: role in redox signaling, vascular function, and diseases". Antioxidants & Redox Signaling. 15 (6): 1583–1606. doi:10.1089/ars.2011.3999. PMC 3151424. PMID 21473702.
  6. Son M, Elliott JL (Jan 2014). "Mitochondrial defects in transgenic mice expressing Cu,Zn superoxide dismutase mutations: the role of copper chaperone for SOD1". Journal of the Neurological Sciences. 336 (1–2): 1–7. doi:10.1016/j.jns.2013.11.004. PMID 24269091. S2CID 7959466.
  7. Nevitt T, Ohrvik H, Thiele DJ (Sep 2012). "Charting the travels of copper in eukaryotes from yeast to mammals". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1823 (9): 1580–1593. doi:10.1016/j.bbamcr.2012.02.011. PMC 3392525. PMID 22387373.
  8. Culotta VC, Klomp LW, Strain J, Casareno RL, Krems B, Gitlin JD (Sep 1997). "The copper chaperone for superoxide dismutase". The Journal of Biological Chemistry. 272 (38): 23469–72. doi:10.1074/jbc.272.38.23469. PMID 9295278.
  9. "Entrez Gene: CCS copper chaperone for superoxide dismutase".
  10. McLoughlin DM, Standen CL, Lau KF, Ackerley S, Bartnikas TP, Gitlin JD, Miller CC (Mar 2001). "The neuronal adaptor protein X11alpha interacts with the copper chaperone for SOD1 and regulates SOD1 activity". The Journal of Biological Chemistry. 276 (12): 9303–7. doi:10.1074/jbc.M010023200. PMID 11115513.

Further reading
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