Laboratory for Structural and Computational Proteomics, Carlos Chagas Institute, Fundação Oswaldo Cruz Paraná (Fiocruz-PR), Curitiba 80320-290, Brazil.
Laboratory of Basic Biology of Stem Cells, Carlos Chagas Institute, Fundação Oswaldo Cruz Paraná (Fiocruz-PR), Curitiba 80320-290, Brazil.
Int J Mol Sci. 2022 Aug 5;23(15):8708. doi: 10.3390/ijms23158708.
The CYFIP2 protein (cytoplasmic FMR1-interacting protein 2) is part of the WAVE regulatory complex (WRC). CYFIP2 was recently correlated to neurological disorders by the association of the R87C variant with early infantile epileptic encephalopathy (EIEE) patients. In this set of syndromes, the epileptic spasms and seizures since early childhood lead to impaired neurological development in children. Inside the WRC, the variant residue is at the CYFIP2 and WAVE1 protein interface. Thus, the hypothesis is that the R87C modification weakens this interaction, allowing the WRC complex's constant activation. This work aimed to investigate the impacts of the mutation on the structure of the WRC complex through molecular dynamics simulation. For that, we constructed WRC models containing WAVE1-NCKAP1 proteins complexed with WT or R87C CYFIP2. Our simulations showed a flexibilization of the loop comprising residues 80-110 due to the loss of contacts between internal residues in the R87C CYFIP2 as well as the key role of residues R/C87, E624, and E689 in structural modification. These data could explain the mechanism by which the mutation impairs the stability and proper regulation of the WRC.
CYFIP2 蛋白（细胞质 FMR1 相互作用蛋白 2）是 WAVE 调节复合物（WRC）的一部分。最近，R87C 变体与早发性婴儿癫痫性脑病（EIEE）患者相关联，将 CYFIP2 与神经紊乱联系起来。在这组综合征中，早发性癫痫痉挛和癫痫发作导致儿童神经发育受损。在 WRC 内，变体残基位于 CYFIP2 和 WAVE1 蛋白的界面。因此，假设 R87C 修饰削弱了这种相互作用，允许 WRC 复合物的持续激活。这项工作旨在通过分子动力学模拟研究突变对 WRC 复合物结构的影响。为此，我们构建了包含 WAVE1-NCKAP1 蛋白与 WT 或 R87C CYFIP2 复合物的 WRC 模型。我们的模拟显示，由于 R87C CYFIP2 内部残基之间的接触丧失以及 R/C87、E624 和 E689 残基在结构修饰中的关键作用，导致包含残基 80-110 的环的柔韧性增加。这些数据可以解释突变如何损害 WRC 的稳定性和适当调节。
