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: Protein kinase domain

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