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J. Biol. Chem., Vol. 278, Issue 43, 41593-41596, October 24, 2003

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The Copper Toxicosis Gene Product Murr1 Directly Interacts with the Wilson Disease Protein^*

Ting Y. Tao, Fengli Liu, Leo Klomp, Cisca Wijmenga, and Jonathan D. Gitlin¶

From the Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110 and the Department of Medical Genetics, University Medical Center Utrecht, 3583EA Utrecht, Netherlands

Copper toxicosis in Bedlington terriers is an autosomal recessive disorder characterized by excessive hepatic copper accumulation in association with a marked decrease in biliary copper excretion. Recent genetic data have revealed that MURR1, a single copy gene on dog chromosome 10q26, is mutated in this disorder. This gene encodes a 190-amino acid open reading frame of unknown function that is highly conserved in vertebrate species. The Wilson disease protein is a copper transporting ATPase shown to play a critical role in biliary copper excretion. Here we demonstrate that the Wilson disease protein directly interacts with the human homologue of Murr1 in vitro and in vivo and that this interaction is mediated via the copper binding, amino terminus of this ATPase. Importantly, this interaction is specific for this copper transporter, a finding consistent with the observation that impaired copper homeostasis in affected terriers is confined to the liver. Our findings reveal involvement of Murr1 in the defined pathway of hepatic biliary copper excretion, suggest a potential mechanism for Murr1 function in this process, and provide biochemical evidence in support of the proposed role of the MURR1 gene in hepatic copper toxicosis.

Received for publication, August 28, 2003 , and in revised form, September 5, 2003.

^* This work was supported by National Institutes of Health Grant DK61763. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Washington University School of Medicine, McDonnell Pediatric Research Bldg., 660 South Euclid Ave., St. Louis, MI 63110. Tel.: 314-286-2764; Fax: 314-286-2893; E-mail: gitlin{at}kids.wustl.edu.

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