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

Area of Science:

• Biochemistry
• Genetics
• Molecular Biology

Background:

• Wilson disease (WD) is a genetic disorder caused by mutations in the ATP7B gene, affecting copper transport and leading to copper accumulation.
• Numerous missense mutations in ATP7B are linked to WD, but genotype-phenotype correlations remain unclear.
• Understanding how specific mutations impact ATP7B function is crucial for predicting WD pathophysiology.

Purpose of the Study:

• To investigate the functional and structural effects of four proposed WD-causing missense mutations in metal-binding domains 5 and 6 of the ATP7B protein.
• To establish genotype-phenotype correlations by analyzing mutation-induced changes in ATP7B copper transport and dynamics.

Main Methods:

• Utilized a traditional yeast assay to assess the copper transport ability of four ATP7B variants.
• Employed molecular dynamics simulations (1.5 μs per variant) to analyze mutation-induced structural dynamic effects at the atomic level.
• Analyzed root-mean square fluctuation and secondary structure content to identify differences in protein dynamics.

Main Results:

• Three of the four investigated ATP7B variants exhibited reduced copper transport ability in the yeast assay.
• Molecular dynamics simulations revealed distinct differences in the structural dynamics of metal-binding domains with mutations.
• Most mutations caused long-range effects, increasing dynamics in the copper-binding loop.

Conclusions:

• Mutation-induced alterations in ATP7B structural dynamics provide a mechanistic explanation for reduced copper transport ability in Wilson disease.
• These findings contribute to understanding genotype-phenotype correlations in WD and may aid future genetic screening.
• The study highlights the importance of assessing protein dynamics to fully comprehend the impact of genetic mutations on disease pathophysiology.