Xie Song, Zuo Ke, De Rubeis Silvia, Ruggerone Paolo, Carloni Paolo
Computational Biomedicine, Institute of Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, Jülich, Germany.
Department of Physics, RWTH Aachen University, Aachen, Germany.
Protein Sci. 2025 Jan;34(1):e5238. doi: 10.1002/pro.5238.
The WAVE regulatory pentameric complex regulates actin remodeling. Two components of it (CYFIP2 and NCKAP1) are encoded by genes whose genetic mutations increase the risk for autism spectrum disorder (ASD) and related neurodevelopmental disorders. Here, we use a newly developed computational protocol and hotspot analysis to uncover the functional impact of these mutations at the interface of the correct isoforms of the two proteins into the complex. The mutations turn out to be located on the surfaces involving the largest number of hotspots of the complex. Most of them decrease the affinity of the proteins for the rest of the complex, but some have the opposite effect. The results are fully consistent with the available experimental data. The observed changes in the WAVE regulatory complex stability might impact on complex activation and ultimately play a role in the aberrant pathway of the complex, leading to the cell derangement associated with the disease.
WAVE调节五聚体复合物调节肌动蛋白重塑。它的两个组分（CYFIP2和NCKAP1）由基因突变会增加自闭症谱系障碍（ASD）及相关神经发育障碍风险的基因编码。在此，我们使用新开发的计算方案和热点分析来揭示这些突变在两种蛋白质正确异构体形成复合物的界面处的功能影响。结果发现这些突变位于复合物中涉及热点数量最多的表面上。其中大多数降低了蛋白质与复合物其他部分的亲和力，但有些则有相反的作用。这些结果与现有的实验数据完全一致。观察到的WAVE调节复合物稳定性变化可能会影响复合物的激活，并最终在复合物的异常途径中起作用，导致与该疾病相关的细胞紊乱。
