Uncovering a membrane-distal conformation of KRAS available to recruit RAF to the plasma membrane

• DOI: 10.1073/pnas.2006504117
• Publication Date: 2020-09-10T23:45:47Z
• Authors: Que N. Van; Cesar A. López; Marco Tonelli; Troy Taylor; Ben Niu; Christopher B. St...; Debsindhu Bhowmik; Timothy H. Tran; Peter H. Frank; Simon Messing; Patrick Alexander; Daniel Scott; Xiaoying Ye; Matt Drew; Oleg Chertov; Mathias Lösche; Arvind Ramanathan; Michael L. Gross; Nicolas W. Hengar...; William M. Westler; John L. Markley; Dhirendra K. Sima...; Dwight V. Nissley; William K. Gillette; Dominic Esposito; Frank McCormick; S. Gnanakaran; Frank Heinrich; Andrew G. Stephen
• Keywords: 0301 basic medicine; 0303 health sciences; neutron reflectometry; RAF RBD; Cell Membrane; Biological Sciences; Molecular Dynamics Simulation; Proto-Oncogene Proteins p21(ras); nuclear magnetic resonance; 03 medical and health sciences; Chemical Sciences; KRAS; 2.1 Biological and endogenous factors; raf Kinases; Biochemistry and Cell Biology; Aetiology; membrane; Cancer

Significance

The proto-oncogene KRAS , a small GTPase, is frequently mutated in pancreatic, colorectal, and lung cancer. These mutations result in elevated levels of the activated guanosine triphosphate-bound form of KRAS. Localized at the plasma membrane, KRAS functions to recruit effectors, predominantly RAF kinase for activation and initiation of the MAPK signaling cascade. Combining computational and biophysical methods we identify a membrane-distal state of the KRAS G-domain that alternates with two previously described membrane-proximal states through dynamic reorganization of the hypervariable region. Comprising about 90% of the ensemble, this membrane-distal state of the G-domain dominates the proximal states and may facilitate KRAS to recruit cytosolic RAF kinase to the membrane by a fly-casting mechanism.