Wilson disease missense mutations in ATP7B affect metal-binding domain structural dynamics
Artikel i vetenskaplig tidskrift, 2019

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 μs 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.

Molecular dynamics

Yeast assay

Copper transport

Wilson disease

Missense mutation


Kumaravel Ponnandai Schanmugavel

Chalmers, Biologi och bioteknik, Kemisk biologi

Ranjeet Kumar

Chalmers, Biologi och bioteknik, Kemisk biologi

Yaozong Li

Universität Zürich

Umeå universitet

Pernilla Wittung Stafshede

Chalmers, Biologi och bioteknik, Kemisk biologi


0966-0844 (ISSN) 1572-8773 (eISSN)

Vol. 32 6 875-885



Farmakologi och toxikologi





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