XIAP is a copper binding protein deregulated in Wilson's disease and other copper toxicosis disorders

Arjmand R. Mufti, Ezra Burstein, Rebecca A. Csomos, Paul C F Graf, John C. Wilkinson, Robert D. Dick, Madhavi Challa, Jae Kyoung Son, Shawn B. Bratton, Grace L. Su, George J. Brewer, Ursula Jakob, Colin S. Duckett

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129 Scopus citations

Abstract

X-linked inhibitor of apoptosis (XIAP), known primarily for its caspase inhibitory properties, has recently been shown to interact with and regulate the levels of COMMD1, a protein associated with a form of canine copper toxicosis. Here, we describe a role for XIAP in copper metabolism. We find that XIAP levels are greatly reduced by intracellular copper accumulation in Wilson's disease and other copper toxicosis disorders and in cells cultured under high copper conditions. Elevated copper levels result in a profound, reversible conformational change in XIAP due to the direct binding of copper to XIAP, which accelerates its degradation and significantly decreases its ability to inhibit caspase-3. This results in a lowering of the apoptotic threshold, sensitizing the cell to apoptosis. These data provide an unsuspected link between copper homeostasis and the regulation of cell death through XIAP and may contribute to the pathophysiology of copper toxicosis disorders.

Original languageEnglish (US)
Pages (from-to)775-785
Number of pages11
JournalMolecular cell
Volume21
Issue number6
DOIs
StatePublished - Mar 17 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Mufti, A. R., Burstein, E., Csomos, R. A., Graf, P. C. F., Wilkinson, J. C., Dick, R. D., Challa, M., Son, J. K., Bratton, S. B., Su, G. L., Brewer, G. J., Jakob, U., & Duckett, C. S. (2006). XIAP is a copper binding protein deregulated in Wilson's disease and other copper toxicosis disorders. Molecular cell, 21(6), 775-785. https://doi.org/10.1016/j.molcel.2006.01.033