Allosteric KRas4B Can Modulate SOS1 Fast and Slow Ras Activation Cycles.

ABSTRACT: Membrane-anchored Ras family proteins are activated by guanine nucleotide exchange factors such as SOS1. The CDC25 domain of SOS1 catalyzes GDP-to-GTP exchange, thereby activating Ras. Here, we aim to decipher the activation mechanism of KRas4B, a significantly mutated oncogene. We perform large-scale molecular dynamics simulations on 12 SOS1 systems, scrutinizing each step in two possible KRas4B activation cycles, fast and slow. To activate KRas4B at the CDC25 catalytic site, the allosteric site in the Ras exchanger motif (REM) domain of SOS1 needs to recruit a (nucleotide-bound) KRas4B molecule. Our simulations indicate that KRas4B-GTP interacts with the REM allosteric site more strongly than with the CDC25 catalytic site, consistent with its allosteric role in the GDP-to-GTP exchange. I

SUBMITTER: Liao TJ 

PROVIDER: S-EPMC6103739 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature