  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.
