Regulation of Membrane Association and Downstream Effector Interaction of K-Ras by Its Hypervariable Region

The small GTPase Ras, a central switch in signal transduction of cell growth, is a crucial element in the development of many forms of cancer. Recent studies have shown that membrane association of Ras is essential to its downstream effector recruitment and signal transduction. Here we investigate the membrane association and interaction of K-Ras4B, the most frequently found Ras isoform in tumor cells, using all-atom molecular dynamics simulations totaling 8.5 μs. We find that the isoform-specific, farnesylated hypervariable region (HVR) of Ras plays an important role in the organization and oligomerization of its globular domain (G-domain) on the surface of the membrane. We show that the overall pose of the Ras G-domain on the membrane can be determined by its HVR. The HVR thus can control downstream effector binding by positioning the G-domain on the membrane in a specific orientation. Furthermore, we observe that the HVR alone already transiently dimerizes in the membrane and recruits negatively charged phosphatidylserine lipids around the K-Ras isoform-specific poly-lysine region. The observed HVR dimerization potentially can initiate the dimerization of the full K-Ras, which is essential for downstream effector signaling via various pathways. These atomistic details behind the molecular mechanism of the HVR provide novel insight into Ras interaction with membrane and its availability for downstream effectors.