Xie Song, Zuo Ke, De Rubeis Silvia, Bonollo Giorgio, Colombo Giorgio, Ruggerone Paolo, Carloni Paolo
Computational Biomedicine, Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, 52428Jülich, Germany.
Department of Physics, RWTH Aachen University, 52056 Aachen, Germany.
J Chem Inf Model. 2025 Jul 28;65(14):7399-7405. doi: 10.1021/acs.jcim.5c01162. Epub 2025 Jul 9.
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.
WAVE调节复合体（WRC）是一种调节肌动蛋白细胞骨架所必需的异五聚体。WRC组分中的基因变异与神经发育障碍（NDDs）风险增加有关，包括自闭症谱系障碍（ASD）。据报道，一些与NDDs相关的错义变异会导致WRC结构域活性C端区域（ACR）异常脱离。通过分子动力学模拟，我们发现这些变异会导致ACR特定螺旋的无序程度类似增加，以及ACR与WRC相互作用减少，无论它们的位置和化学性质如何。这些可能有助于ACR脱离。我们进一步证明了它们对复合体大规模运动的影响。综上所述，这些结果确实表明，与NDD相关变异相关的不同修饰会导致WRC结构动力学发生类似变化。
