Arl2-mediated allosteric release of farnesylated kras4b from shuttling factor pde delta

Abstract

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 PDE delta shuttling protein through their farnesylated hypervariable regions (HVRs). The docking of their famesyl (and to a lesser extent geranylgeranyl) in the hydrophobic pocket of PDE delta'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 PDE delta. 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 PDE delta. We simulated ternary Arl2 PDE delta KRas4B HVR complexes and observed that Arl2 binding weakens the PDE delta farnesylated HVR interaction. Our detailed analysis showed that allosteric changes (involving beta 6 of PDE delta and additional PDE delta residues) compress the hydrophobic PDE delta pocket and push the HVR out. Mutating PDE delta residues that mediate allosteric changes in PDE delta 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.