Impact of Genetic Variants Associated with Neurodevelopmental Disorders on the WAVE Regulatory Complex

The WAVE regulatory complex (WRC) is a heteropentamer necessary for the regulation of actin cytoskeleton. Genetic variants in components of the WRC have been associated with increased risk for neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD). Some of the missense variants associated with NDDs have been reported to cause aberrant detachment of the WRC domain active C-terminal region (ACR). Using molecular dynamics simulations, we show that these variants cause a similar increase in disorder in a specific helix of ACR as well as a decrease in ACR/WRC interactions, irrespective of their position and chemical nature. These might assist ACR detachment. We further demonstrate their impact on the large-scale motions of the complex. Taken together, these results do suggest that different modifications associated with the NDD-associated variants converge on similar changes to the structural dynamics of the WRC.