Effector Binding Sequentially Alters KRAS Dimerization on the Membrane: New Insights Into RAS-Mediated RAF Activation.

ABSTRACT: RAS proteins are peripheral membrane GTPases that activate multiple downstream effectors for cell proliferation and differentiation. The formation of a signaling RAS-RAF complex at the plasma membrane is implicated in a quarter of all human cancers; however, the underlying mechanism remains unclear. In this work, nanodisc platforms and paramagnetic relaxation enhancement (PRE) analyses to determine the structure of a hetero-tetrameric complex comprising KRAS and the RAS-binding domain (RBD) and cysteine-rich domain (CRD) of activated RAF1 are employed. The binding of the RBD or RBD-CRD differentially alters the dimerization modes of KRAS on both anionic and neutral membranes, validated by interface-specific mutagenesis. Notably, the RBD binding allosterically generated two distinct KRAS di

SUBMITTER: Lee SY 

PROVIDER: S-EPMC11481233 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature