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.
As two counterparts of a protein complex, K-Ras4B and C-Raf CRD interact with membrane in a competitive manner due to topological restriction, presenting two major dynamic membrane-associated states.