Association of Raf kinase with activated Ras triggers downstream signaling cascades toward regulating transcription in the cells’ nucleus. Dysregulation of Ras–Raf signaling stimulates cancers. We investigate the C-Raf RBD and CRD regions when bound to oncogenic K-Ras4B at the membrane. All-atom molecular dynamics simulations suggest that the membrane plays an integral role in regulating the configurational ensemble of the complex. Remarkably, the complex samples a few states dynamically, reflecting a competition between C-Raf CRD- and K-Ras4B- membrane interactions. This competition arises because the interaction between the RBD and K-Ras is strong while the linker between the RBD and CRD is short. Such a mechanism maintains a modest binding for the overall complex at the membrane and is expected to facilitate fast signaling processes. Competition of protein–membrane contacts is likely a common mechanism for other multiprotein complexes, if not multidomain proteins at membranes.

中文翻译：

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“拔河比赛”维持着动态的蛋白质膜复合物：在阴离子膜上与K-Ras4B结合的C-Raf RBD-CRD的分子动力学模拟。

Raf激酶与激活的Ras的结合会触发下游信号传导级联，以调节细胞核中的转录。Ras–Raf信号传导异常会刺激癌症。当在膜上与致癌的K-Ras4B结合时，我们研究了C-Raf RBD和CRD区。全原子分子动力学模拟表明，膜在调节复合物的构型整体中起着不可或缺的作用。值得注意的是，该复合物动态地采样了一些状态，反映了C-Raf CRD-和K-Ras4B-膜相互作用之间的竞争。之所以出现这种竞争，是因为RBD与K-Ras之间的相互作用很强，而RBD与CRD之间的连接子却很短。这种机制对膜上的整个复合物保持适度的结合，并有望促进快速的信号传导过程。