XIAP Is a Copper Binding Protein Deregulated in Wilson's Disease and Other Copper Toxicosis Disorders

Division of Pharmacology & Toxicology, University of Texas at Austin, Austin, Texas, United States
Molecular Cell (Impact Factor: 14.02). 04/2006; 21(6):775-85. DOI: 10.1016/j.molcel.2006.01.033
Source: PubMed


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.

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    • "Elevated copper levels result in a profound, reversible conformational change in XIAP, which accelerates degradation and significantly decreases the ability of XIAP to inhibit caspase-3 (Mufti et al. 2006, 2007). The observation of periportal copper accumulation in our patient is likely to be secondary to cholestasis; however, copper accumulation has been associated with the initiation of apoptosis via XIAP and mitochondrial oxidative stress. "
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    • "However, it is known that copper is involved in the production toxic free radicals (Samuele et al., 2005), and excess copper has been shown to inhibit Inhibitor of apoptosis proteins (IAPs) caused by toxic deposits of intracellular copper (Mufti et al., 2006). WD is a progressive disorder and was ultimately a fatal disease until the discovery of the first treatment in 1951 (Denny- Brown and Porter, 1951). "
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    • "X-linked inhibitor of apoptosis (XIAP), an anti-apoptotic protein, has recently been shown to regulate copper homeostasis. XIAP levels are greatly reduced in cells cultured under high copper conditions [23]. XIAP exerts its role in two different ways [24]: First, XIAP, when bounded with copper, will lead to its conformational changes, which results in increased susceptibility to apoptotic stimuli; second, XIAP promotes the degradation of COMMD1 by protoeasome. "
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