RT Journal Article
SR Electronic
T1 A “Tug of War” maintains a dynamic protein-membrane complex as shown in all-atom simulations of C-Raf RBD-CRD bound to K-Ras4B at an anionic membrane
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 181347
DO 10.1101/181347
A1 Zhen-Lu Li
A1 Priyanka Prakash
A1 Matthias Buck
YR 2017
UL http://biorxiv.org/content/early/2017/12/04/181347.abstract
AB Association of Raf kinase with activated Ras triggers downstream signaling cascades, towards 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 and the linker between the RBD and CRD is short. This study reveals a mechanism that maintains a modest binding for the overall complex at the membrane to facilitate fast signaling processes. It is likely a common mechanism for other multi-protein, if not multidomain proteins at membranes.