Arl2-Mediated Allosteric Release of Farnesylated KRas4B from Shuttling Factor PDEδ

Proper localization of Ras proteins at the plasma membrane (PM) is crucial for their functions. To get to the PM, KRas4B and some other Ras family proteins bind to the PDEδ shuttling protein through their farnesylated hypervariable regions (HVRs). The docking of their farnesyl (and to a lesser extent geranylgeranyl) in the hydrophobic pocket of PDEδ's stabilizes the interaction. At the PM, guanosine 5′-triphosphate (GTP)-bound Arf-like protein 2 (Arl2) assists in the release of Ras from the PDEδ. However, exactly how is still unclear. Using all-atom molecular dynamics simulations, we unraveled the detailed mechanism of Arl2-mediated release of KRas4B, the most abundant oncogenic Ras isoform, from PDEδ. We simulated ternary Arl2-PDEδ-KRas4B HVR complexes and observed that Arl2 binding weakens the PDEδ-farnesylated HVR interaction. Our detailed analysis showed that allosteric changes (involving β6 of PDEδ and additional PDEδ residues) compress the hydrophobic PDEδ pocket and push the HVR out. Mutating PDEδ residues that mediate allosteric changes in PDEδ terminates the release process. Mutant Ras proteins are enriched in human cancers, with currently no drugs in the clinics. This mechanistic account may inspire efforts to develop drugs suppressing oncogenic KRas4B release.