Biophysical mechanism for Ras-nanocluster formation and signaling in plasma membrane

TL;DR

This paper introduces a biophysical model explaining Ras nanocluster formation through short-range attraction and long-range repulsion, aligning with experimental data and suggesting a role in high-fidelity cell signaling.

Contribution

The study presents a novel biophysical model of Ras clustering that does not rely on the assumption of a constant cluster/monomer ratio, supported by Monte Carlo simulations.

Findings

Successfully reproduces Ras clustering across various expression levels

Does not depend on lipid raft assumptions

Predicts Ras nanoclusters as high-fidelity signaling converters

Abstract

Ras GTPases are lipid-anchored G proteins which play a fundamental role in cell signaling processes. Electron micrographs of immunogold-labeled Ras have shown that membrane-bound Ras molecules segregate into nanocluster domains. Several models have been developed in attempts to obtain quantitative descriptions of nanocluster formation, but all have relied on assumptions such as a constant, expression-level independent ratio of Ras in clusters to Ras monomers (cluster/monomer ratio). However, this assumption is inconsistent with the law of mass action. Here, we present a biophysical model of Ras clustering based on short-range attraction and long-range repulsion between Ras molecules in the membrane. To test this model, we performed Monte Carlo simulations and compared statistical clustering properties with experimental data. We find that we can recover the experimentally-observed clustering across a range of Ras expression levels, without assuming a constant cluster/monomer ratio or the existence of lipid rafts. In addition, our model makes predictions about the signaling properties of Ras nanoclusters in support of the idea that Ras nanoclusters act as an analog-digital-analog converter for high fidelity signaling.