Uncovering a membrane-distal conformation of KRAS available to recruit RAF to the plasma membrane
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
DOI:
10.1073/pnas.2006504117
Publication Date:
2020-09-10T23:45:47Z
AUTHORS (29)
ABSTRACT
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.
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