Copper-induced conformational changes in the N-terminal domain of the Wilson disease copper-transporting ATPase

Michael DiDonato, Hua-Fen Hsu, Suree Narindrasorasak, Lawrence Que, Bibudhendra Sarkar

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

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 aminoterminal 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.

Original languageEnglish
Pages (from-to)1890-1896
Number of pages7
JournalBiochemistry
Volume39
Issue number7
DOIs
Publication statusPublished - 2000 Feb 22

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Hepatolenticular Degeneration
Copper
Adenosine Triphosphatases
X-Ray Absorption Spectroscopy
Binding Sites
copper-transporting ATPases
Poisons
X ray absorption spectroscopy
Cysteine
Liver
Brain
Proteins
Kidney
Tissue

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

DiDonato, Michael ; Hsu, Hua-Fen ; Narindrasorasak, Suree ; Que, Lawrence ; Sarkar, Bibudhendra. / Copper-induced conformational changes in the N-terminal domain of the Wilson disease copper-transporting ATPase. In: Biochemistry. 2000 ; Vol. 39, No. 7. pp. 1890-1896.
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Copper-induced conformational changes in the N-terminal domain of the Wilson disease copper-transporting ATPase. / DiDonato, Michael; Hsu, Hua-Fen; Narindrasorasak, Suree; Que, Lawrence; Sarkar, Bibudhendra.

In: Biochemistry, Vol. 39, No. 7, 22.02.2000, p. 1890-1896.

Research output: Contribution to journalArticle

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