Dynamic regulation of RAS and RAS signaling

Abstract

RAS proteins regulate most aspects of cellular physiology. They are mutated in 30% of human cancers and 4% of developmental disorders termed Rasopathies. They cycle between active GTP-bound and inactive GDP-bound states. When active, they can interact with a wide range of effectors that control fundamental biochemical and biological processes. Emerging evidence suggests that RAS proteins are not simple on/off switches but sophisticated information processing devices that compute cell fate decisions by integrating external and internal cues. A critical component of this compute function is the dynamic regulation of RAS activation and downstream signaling that allows RAS to produce a rich and nuanced spectrum of biological outputs. We discuss recent findings how the dynamics of RAS and its downstream signaling is regulated. Starting from the structural and biochemical properties of wild-type and mutant RAS proteins and their activation cycle, we examine higher molecular assemblies, effector interactions and downstream signaling outputs, all under the aspect of dynamic regulation. We also consider how computational and mathematical modeling approaches contribute to analyze and understand the pleiotropic functions of RAS in health and disease.

Mechanism-Based Redesign of GAP to Activate Oncogenic Ras

“…Nevertheless, despite that the current mechanism seems highly likely, we cannot exclude larger structural changes that might accompany, or prelude, the second proton transfer. This is also possible, considering available structural data, as GDP-bound Ras has a distinct switch I-II domain conformation, 27 and such a conformational change must take place after the cleavage of the γ-phosphate. However, the current QM/MM-based methods would not be able to capture such significant structural rearrangements, even if the timescale is fast, and future work will be needed to evaluate this mechanism.…”

“…However, key oncogenic mutations render Ras catalytically inactive, and thus, Ras stays in its active signaling, GTP-bound form. 27 In a recent experimental work, the RGS3 domain, which serves as GAP for other G proteins, was found to recover catalytic activity of G12C Ras compared with intrinsic or NF1catalyzed hydrolysis. 28 This validates an approach that targets oncogenic Ras by restoring its activity, instead of modulating the signaling by the inhibition of downstream effectors.…”

“…To turn signaling off, , Ras hydrolyses GTP to GDP with the help of GTPase-activating proteins (GAPs), typically p120GAP or Ras p21. , GAP completes the environment around the active site (Figure A); it contains key conserved motifs, including an arginine finger (Figure B) to enable effective catalysis. However, key oncogenic mutations render Ras catalytically inactive, and thus, Ras stays in its active signaling, GTP-bound form …”

Redesigned GAP to activate oncogenic GAP

“…However, key oncogenic mutations render Ras catalytically inactive, and thus Ras stays in its active signaling, GTP-bound form. 25 In a recent experimental work, the RGS3 domain, which serves as GAP for other G-proteins, was found to recover catalytic activity of G12C Ras compared with intrinsic or NF1 catalyzed hydrolysis. 26 This open an avenue for targeting oncogenic Ras by restoring its activity, instead of modulating the signaling by the inhibition of interactions with downstream effectors.…”

“…Nevertheless, despite that the current mechanism seems highly likely, we cannot exclude larger structural changes that might accompany, or prelude, the second proton transfer. This is also possible, considering available structural data, as GDP-bound Ras has a distinct switch I-II domain conformation, 59 and such a conformational change must take place after the cleavage of the gamma phosphate. However, the current QM/MM-based methods would not be able to capture such significant structural rearrangements, even if the timescale is fast, and future work will be needed to evaluate this mechanism.…”