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Author Spotlight: Exploring Autism Spectrum Disorder Symptoms in Fruit Flies — Genetic Models and Behavioral Tests
Published on: September 6, 2024
Common characteristics of variants linked to autism spectrum disorder in the WAVE regulatory complex
Song Xie1,2, Ke Zuo1,3,4, Silvia De Rubeis5,6,7,8,9,10
1Computational Biomedicine, Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, Jülich, Germany.
Abstract:
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 all 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.
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