Wilson disease missense mutations in ATP7B affect metal-binding domain structural dynamics
Journal article, 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

Author

Kumaravel Ponnandai Schanmugavel

Chalmers, Biology and Biological Engineering, Chemical Biology

Ranjeet Kumar

Chalmers, Biology and Biological Engineering, Chemical Biology

Yaozong Li

University of Zürich

Umeå University

Pernilla Wittung Stafshede

Chalmers, Biology and Biological Engineering, Chemical Biology

Biometals

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

Vol. 32 6 875-885

Subject Categories

Neurosciences

Pharmacology and Toxicology

DOI

10.1007/s10534-019-00219-y

PubMed

31598802

More information

Latest update

6/13/2022