Binding of Copper(I) by the Wilson Disease Protein and Its Copper Chaperone

Amy K. Wernimont, Liliya A. Yatsunyk, Amy C. Rosenzweig*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

80 Scopus citations


The Wilson disease protein (WND) is a transport ATPase involved in copper delivery to the secretory pathway. Mutations in WND and its homolog, the Menkes protein, lead to genetic disorders of copper metabolism. The WND and Menkes proteins are distinguished from other P-type ATPases by the presence of six soluble N-terminal metal-binding domains containing a conserved CXXC metal-binding motif. The exact roles of these domains are not well established, but possible functions include exchanging copper with the metallochaperone Atox1 and mediating copper-responsive cellular relocalization. Although all six domains can bind copper, genetic and biochemical studies indicate that the domains are not functionally equivalent. One way the domains could be tuned to perform different functions is by having different affinities for Cu(I). We have used isothermal titration calorimetry to measure the association constant (Ka) and stoichiometry (n) values of Cu(I) binding to the WND metal-binding domains and to their metallochaperone Atox1. The association constants for both the chaperone and target domains are ∼105 to 106 M-1, suggesting that the handling of copper by Atox1 and copper transfer between Atox1 and WND are under kinetic rather than thermodynamic control. Although some differences in both n and Ka values are observed for variant proteins containing less than the full complement of six metal-binding domains, the data for domains 1-6 were best fitted with a single site model. Thus, the individual functions of the six WND metal-binding domains are not conferred by different Cu(I) affinities but instead by fold and electrostatic surface properties.

Original languageEnglish (US)
Pages (from-to)12269-12276
Number of pages8
JournalJournal of Biological Chemistry
Issue number13
StatePublished - Mar 26 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry
  • Cell Biology


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