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

Department of Pathology, University of Michigan Medical School, Ann Arbor, 48109, USA.
Molecular Cell (Impact Factor: 14.02). 04/2006; 21(6):775-85. DOI: 10.1016/j.molcel.2006.01.033
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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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Available from: Ezra Burstein, Oct 05, 2015
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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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    ABSTRACT: Defects in the mitochondrial respiratory chain can induce a heterogeneous range of clinical and biochemical manifestations. Hepatic involvement includes acute fulminant hepatic failure, microvesicular steatosis, neonatal non-alloimmune haemochromatosis and cirrhosis. Recently pathogenic mutations in tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase (TRMU) gene (OMIM 610230) have been demonstrated to cause transient infantile liver failure (OMIM 613070). The human TRMU gene encodes a mitochondrial protein, 5-methylaminomethyl-2-thiouridylate methyltransferase, whose molecular function is that of mitochondrial tRNA modification.We report an infant who presented with acute liver failure, in whom we observed hepatic copper intoxication and cirrhosis on liver biopsy. We postulate that the hepatic copper intoxication observed in our patient is most likely a secondary event associated with cholangiopathy. Periportal copper accumulation has been implicated in causing secondary mitochondrial dysfunction; the impact of copper accumulation in patients with TRMU mutations is unclear and warrants long-term clinical follow-up.
    02/2015; 21. DOI:10.1007/8904_2014_402
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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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    ABSTRACT: Copper, iron, and zinc are just three of the main biometals critical for correct functioning of the central nervous system (CNS). They have diverse roles in many functional processes including but not limited to enzyme catalysis, protein stabilization, and energy production. The range of metal concentrations within the body is tightly regulated and when the balance is perturbed, debilitating effects ensue. Homeostasis of brain biometals is mainly controlled by various metal transporters and metal sequestering proteins. The biological roles of biometals are vastly reviewed in the literature with a large focus on the connection to neurological conditions associated with ageing. Biometals are also implicated in a variety of debilitating inherited childhood disorders, some of which arise soon following birth or as the child progresses into early adulthood. This review acts to highlight what we know about biometals in childhood neurological disorders such as Wilson's disease (WD), Menkes disease (MD), neuronal ceroid lipofuscinoses (NCLs), and neurodegeneration with brain iron accumulation (NBIA). Also discussed are some of the animal models available to determine the pathological mechanisms in these childhood disorders, which we hope will aid in our understanding of the role of biometals in disease and in attaining possible therapeutics in the future.
    Frontiers in Aging Neuroscience 03/2013; 5:14. DOI:10.3389/fnagi.2013.00014 · 4.00 Impact Factor
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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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    ABSTRACT: Wilson disease is an autosomal recessive disorder of copper metabolism. Diagnosis depends primarily on clinical features, biochemical parameters and the presence of the Kayser-Fleischer ring. Genetic analysis for mutations within ATP7B is a convincing diagnostic tool. The traditional treatment for WD includes chelation of excessive copper accumulation and reduction of copper intake. Medical therapy is effective but WD is not yet curable. Liver transplantation is especially helpful for patients who fail to respond to medical therapy or present with fulminant liver failure, although evaluation of its long-term effect are still in need.
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