Copper-Induced Conformational Changes in the N-Terminal Domain of the Wilson Disease Copper-Transporting ATPase

The Wilson disease copper-transporting ATPase plays a critical role in the intracellular trafficking of copper. Mutations in this protein lead to the accumulation of a toxic level of copper in the liver, kidney, and brain followed by extensive tissue damage and death. The ATPase has a novel amino-te...

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Bibliographic Details
Published in:Biochemistry (Easton) 2000-02, Vol.39 (7), p.1890-1896
Main Authors: DiDonato, Michael, Hsu, Hua-Fen, Narindrasorasak, Suree, Que, Lawrence, Sarkar, Bibudhendra
Format: Article
Language:English
Subjects:
Adenosine Triphosphatases - chemistry
Adenosine Triphosphatases - metabolism
Carrier Proteins - chemistry
Carrier Proteins - metabolism
Cation Transport Proteins
Circular Dichroism
Copper - chemistry
Copper - metabolism
Copper-transporting ATPases
Humans
Models, Biological
Peptide Fragments - chemistry
Peptide Fragments - metabolism
Protein Binding
Protein Conformation
Protein Structure, Secondary
Protein Structure, Tertiary
Spectrum Analysis
X-Rays
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Summary:The Wilson disease copper-transporting ATPase plays a critical role in the intracellular trafficking of copper. Mutations in this protein lead to the accumulation of a toxic level of copper in the liver, kidney, and brain followed by extensive tissue damage and death. The ATPase has a novel amino-terminal domain (∼70 kDa) which contains six repeats of the copper binding motif GMTCXXC. We have expressed and characterized this domain with respect to the copper binding sites and the conformational consequences of copper binding. A detailed analysis of this domain by X-ray absorption spectroscopy (XAS) has revealed that each binding site ligates copper in the +1 oxidation state using two cysteine side chains with distorted linear geometry. Analysis of copper-induced conformational changes in the amino-terminal domain indicates that both secondary and tertiary structure changes take place upon copper binding. These copper-induced conformational changes could play an important role in the function and regulation of the ATPase in vivo. In addition to providing important insights on copper binding to the protein, these results suggest a possible mechanism of copper trafficking by the Wilson disease ATPase.
ISSN:0006-2960
1520-4995
DOI:10.1021/bi992222j