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Wilson disease missense mutations in ATP7B affect metal-binding domain structural dynamics
Umeå University, Faculty of Science and Technology, Department of Chemistry. Department of Biochemistry, University of Zurich, 8006 Zurich, Switzerland.
2019 (English)In: Biometals, ISSN 0966-0844, E-ISSN 1572-8773, Vol. 32, no 6, p. 875-885Article in journal (Refereed) Published
Abstract [en]

Wilson disease (WD) is caused by mutations in the gene for ATP7B, a copper transport protein that regulates copper levels in cells. A large number of missense mutations have been reported to cause WD but genotype-phenotype correlations are not yet established. Since genetic screening for WD may become reality in the future, it is important to know how individual mutations affect ATP7B function, with the ultimate goal to predict pathophysiology of the disease. To begin to assess mechanisms of dysfunction, we investigated four proposed WD-causing missense mutations in metal-binding domains 5 and 6 of ATP7B. Three of the four variants showed reduced ATP7B copper transport ability in a traditional yeast assay. To probe mutation-induced structural dynamic effects at the atomic level, molecular dynamics simulations (1.5 mu s simulation time for each variant) were employed. Upon comparing individual metal-binding domains with and without mutations, we identified distinct differences in structural dynamics via root-mean square fluctuation and secondary structure content analyses. Most mutations introduced distant effects resulting in increased dynamics in the copper-binding loop. Taken together, mutation-induced long-range alterations in structural dynamics provide a rationale for reduced copper transport ability.

Place, publisher, year, edition, pages
Springer, 2019. Vol. 32, no 6, p. 875-885
Keywords [en]
Wilson disease, Missense mutation, Copper transport, Molecular dynamics, Yeast assay
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-167061DOI: 10.1007/s10534-019-00219-yISI: 000504206300005PubMedID: 31598802OAI: oai:DiVA.org:umu-167061DiVA, id: diva2:1383993
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationAvailable from: 2020-01-09 Created: 2020-01-09 Last updated: 2020-01-09Bibliographically approved

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