Presence or Absence of Ras Dimerization Shows Distinct Kinetic Signature in Ras-Raf Interaction

Abstract

Initiations of cell signaling pathways often occur through the formation of multiprotein complexes that form through protein-protein interactions. Therefore, detecting their presence is central to understanding the function of a cell signaling pathway, aberration of which often leads to fatal diseases, including cancers. However, the multiprotein complexes are often difficult to detect using microscopes due to their small sizes. Therefore, currently, their presence can be only detected through indirect means. In this article, we propose to investigate the presence or absence of protein complexes through some easily measurable kinetic parameters, such as activation rates. As a proof of concept, we investigate the Ras-Raf system, a wellcharacterized cell signaling system. It has been hypothesized that Ras dimerization is necessary to create activated Raf dimers. Although there are circumstantial evidences supporting the Ras dimerization hypothesis, direct proof of Ras dimerization is still inconclusive. In the absence of conclusive direct experimental proof, this hypothesis can only be examined through indirect evidences of Ras dimerization. In this article, using a multiscale simulation technique, we provide multiple criteria that distinguishes an activation mechanism involving Ras dimerization from another mechanism that does not involve Ras dimerization. The provided criteria will be useful in the investigation of not only Ras-Raf interaction but also other two-protein interactions.

Stochastic Spatiotemporal Simulation of a General Reaction System

“…In this section we examine a model reaction-diffusion system motivated by quantifying the effect that protein complex formation may have on enzymatic activity simply through the change in diffusivity that results from forming a macromolecular assembly. The effect of spatiotemporal correlations introduced by decreased diffusion rates or the restriction that comes from reactions confined to a 2-D surface is known to plan an important role in the kinetics of reacting systems [30,31,32,33,34]. Rebinding events which can occur with slow diffusion or poor mixing can lead to different macroscopic behavior than predicted from intrinsic microscopic rates [35,36].…”

Lifetime of actin-dependent protein nanoclusters

“…KRAS4B (RAS henceforth) is a peripheral membrane protein in human cells that interacts with the kinase RAF1 (RAF henceforth) to control cellular growth, differentiation, and proliferation ( 25 , 26 , 27 ). Mutated RAS and RAF is the underlying cause of 30% of all known cancers ( 28 , 29 ). In this paper, through the application of our general model, we have shown how oncogenic mutations in RAS lead to cancers.…”