Does Ras Activate Raf and PI3K Allosterically?

Ruth Nussinov,Chung-Jung Tsai,Hyunbum Jang

doi:10.3389/fonc.2019.01231

Abstract

The mechanism through which oncogenic Ras activates its effectors is vastly important to resolve. If allostery is at play, then targeting allosteric pathways could help in quelling activation of MAPK (Raf/MEK/ERK) and PI3K (PI3K/Akt/mTOR) cell proliferation pathways. On the face of it, allosteric activation is reasonable: Ras binding perturbs the conformational ensembles of its effectors. Here, however, we suggest that at least for Raf, PI3K, and NORE1A (RASSF5), that is unlikely. Raf's long disordered linker dampens effective allosteric activation. Instead, we suggest that the high-affinity Ras–Raf binding relieves Raf's autoinhibition, shifting Raf's ensemble from the inactive to the nanocluster-mediated dimerized active state, as Ras also does for NORE1A. PI3K is recruited and allosterically activated by RTK (e.g., EGFR) at the membrane. Ras restrains PI3K's distribution and active site orientation. It stabilizes and facilitates PIP2 binding at the active site and increases the PI3K residence time at the membrane. Thus, RTKs allosterically activate PI3Kα; however, merging their action with Ras accomplishes full activation. Here we review their activation mechanisms in this light and draw attention to implications for their pharmacology.

Highlights

Is allostery driving Ras activation of its effectors? The presumption that this is the case is easy to understand
NORE1A) tumor suppressor (Figure 1). We suggest that these Ras effectors are not activated via allosteric activation through Ras interaction
Rather than allostery activating NORE1A to promote its activation of MST kinase, the high affinity of the SARAH heterodimer drives the equilibrium toward NORE1A open active state, driving mammalian sterile 20like kinase 1/2 (MST1/2) kinase activation via population shift

Summary

INTRODUCTION

Is allostery driving Ras activation of its effectors? The presumption that this is the case is easy to understand. Active Ras binds its effectors, and direct binding always perturbs the structures, initiating and promoting dynamic and at least some conformational changes [1,2,3,4]. Even though not directly observed, the premise in the community has been that this is likely to be the case. We overview PI3Kα and Raf activation, as well as activation of Ras association domain family 5 (RASSF5, a.k.a. NORE1A) tumor suppressor (Figure 1). We suggest that these Ras effectors are not activated via allosteric activation through Ras interaction. In the case of Raf, a long disordered linker joins the kinase domain with the regulatory domain containing the Ras binding domain (RBD) and

Allostery in Ras Activation

CONCLUDING REMARKS