Common characteristics of variants linked to autism spectrum disorder in the WAVE regulatory complex

Six variants associated with autism spectrum disorder (ASD) abnormally activate the WASP-family Verprolin-homologous protein (WAVE) regulatory complex (WRC), a critical regulator of actin dynamics. This abnormal activation may contribute to the pathogenesis of this disorder. Using molecular dynamics (MD) simulations, we recently investigated the structural dynamics of wild-type (WT) WRC and R87C, A455P, and Q725R WRC disease-linked variants. Here, by extending MD simulations to I664M, E665K, and D724H WRC, we suggest that <i>all</i> of the mutations weaken the interactions and affect intra-complex allosteric communication between the WAVE1 active C-terminal region (ACR) and the rest of the complex. This might contribute to an abnormal complex activation, a hallmark of WRC-linked ASD. In addition, all mutants but I664M destabilize the ACR V-helix and increase the participation of ACR in large-scale movements. All these features may also abnormally influence the inactive WRC toward a dysfunctional state. We hypothesize that small-molecule ligands counteracting these effects may help restore normal WRC regulation in ASD-related variants.