Zinc-mediated interaction of copper chaperones through their heavy-metal associated domains

Yoshiaki Furukawa, Kyoka Matsumoto, Kenta Nakagome, Atsuko Shintani, Kaori Sue

Research output: Contribution to journalArticlepeer-review


Background: A copper chaperone CCS is a multi-domain protein that supplies a copper ion to Cu/Zn-superoxide dismutase (SOD1). Among the domains of CCS, the N-terminal domain (CCSdI) belongs to a heavy metal-associated (HMA) domain, in which a Cys-x-x-Cys (CxxC) motif binds a heavy metal ion. It has hence been expected that the HMA domain in CCS has a role in the metal trafficking; however, the CxxC motif in the domain is dispensable for supplying a copper ion to SOD1, leaving an open question on roles of CCSdI in CCS. Methods: To evaluate protein-protein interactions of CCS through CCSdI, yeast two-hybrid assay, a pull-down assay using recombinant proteins, and the analysis with fluorescence resonance energy transfer were performed. Results: We found that CCS specifically interacted with another copper chaperone HAH1, a HMA domain protein, through CCSdI. The interaction between CCSdI and HAH1 was not involved in the copper supply from CCS to SOD1 but was mediated by a zinc ion ligated with Cys residues of the CxxC motifs in CCSdI and HAH1. Conclusion: While physiological significance of the interaction between copper chaperones awaits further investigation, we propose that CCSdI would have a role in the metal-mediated interaction with other proteins including heterologous copper chaperones.

Original languageEnglish
Article number127111
JournalJournal of Trace Elements in Medicine and Biology
Publication statusPublished - 2023 Jan


  • Copper
  • Copper chaperone
  • Heavy-metal associated domain
  • SOD1
  • Yeast two-hybrid
  • Zinc

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Inorganic Chemistry


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