Zinc binding to the NH2-terminal domain of the Wilson disease copper-transporting ATPase. Implications for in vivo metal ion-mediated regulation of ATPase activity

Michael Didonato, Jingyan Zhang, Lawrence Que, Bibudhendra Sarkar

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25 Scopus citations

Abstract

Mutations in the Wilson disease copper transporting, P-type ATPase lead to the accumulation of toxic levels of copper in the liver, brain, and kidney causing extensive tissue damage and eventual death. The NH2-terminal domain (∼70 kDa), which contains six copies of the heavy metal-associated repeat GMT/HCXXC, is also able to bind zinc. We have used circular dichroism (CD) and x-ray absorption spectroscopy (XAS) to characterize zinc binding to the NH2-terminal metal-binding domain. These studies have revealed that zinc is able to bind to this domain with a stoichiometry of 6:1, and upon binding, induces conformational changes in the NH2-terminal domain. These conformational changes are completely different from those previously observed for copper binding to the domain and lead to an overall loss of secondary structure in the domain. The XAS spectra indicate that zinc is ligated primarily by nitrogen atoms and therefore has low affinity for the heavy metal-associated repeats where copper has been shown to bind. The differences between zinc and copper binding may serve as the basis for the metal-ion mediated regulation of the ATPase in vivo.

Original languageEnglish (US)
Pages (from-to)13409-13414
Number of pages6
JournalJournal of Biological Chemistry
Volume277
Issue number16
DOIs
StatePublished - Apr 19 2002

Bibliographical note

Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.

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