Ras proteins are classical members of small GTPases, promoting cell proliferation and survival, and controlling signal transduction. K-Ras4B is the most abundant oncogenic isoform. In cancer, there are two independent pathways in tumor proliferation: one includes MAPK/ERK and PI3K/Akt/mTOR; and the other consists of Hippo and WNT pathways leading to the expression (or activation) of YAP1 and c-Myc, respectively. KRAS contributes through the first. MAPK and PI3K signaling pathways act in the early and late G1 cell cycle. Hippo and WNT are independent and corresponding pathways to MAPK and PI3K phases. In calcium- and calmodulin (CaM)-rich environments, such as ductal tissues, CaM modulates MAPK and fully stimulates the PI3Kα/Akt/mTOR pathway. Ca2+/CaM recruits PI3Kα through interaction with its n/cSH2 domains and sequesters K-Ras4B from the membrane, organizing a CaM/K-Ras4B/PI3Kα ternary complex. Ca2+/CaM can replace the missing receptor tyrosine kinase (RTK) signal, acting to fully activate PI3Kα. Here using MD simulations, we observed that CaM prefers to bind unfolded K-Ras4B HVRs; not α-helical HVRs. The interaction involves all three domains of CaM including the central linker and both lobes. CaM specifically targets the highly polybasic anchor region of the K-Ras4B HVR that stably wraps around CaM’s acidic linker. The docking of the farnesyl group to the hydrophobic pockets located at both lobes of CaM further enhances the stability of the CaM/HVR complex. Both CaM and K-Ras4B HVR are highly flexible molecules, suggesting that their interactions are highly dynamic with flexible-body motion. We anticipate that the flexible-body interaction is required to extract K-Ras4B from the membrane, since conformational plasticity enables CaM to orient efficiently to the polybasic HVR anchor, which is partially diffused into the liquid-phase membrane. Our structural model of CaM/K-Ras4B HVR association provides plausible clues of CaM’s regulatory action in PI3Kα activation involving the ternary complex in cell proliferation signaling by oncogenic K-Ras.

High affinity interaction of calmodulin with K-Ras4B implicating membrane extraction

254th National Meeting (2017)

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