Lifetime of actin-dependent protein nanoclusters

Abstract

Protein nanoclusters (PNCs) are dynamic collections of a few proteins that spatially organize in nanometer length clusters. PNCs are one of the principal forms of spatial organization of membrane proteins and they have been shown or hypothesized to be important in various cellular processes, including cell signaling. PNCs show remarkable diversity in size, shape, and lifetime. In particular, the lifetime of PNCs can vary over a wide range of timescales. The diversity in size and shape can be explained by the interaction of the clustering proteins with the actin cytoskeleton or the lipid membrane, but very little is known about the processes that determine the lifetime of the nanoclusters. In this paper, using mathematical modelling of the cluster dynamics, we model the biophysical processes that determine the lifetime of actin-dependent PNCs. In particular, we investigated the role of actin aster fragmentation, which had been suggested to be a key determinant of the PNC lifetime, and found that it is important only for a small class of PNCs. A simple extension of our model allowed us to investigate the kinetics of protein-ligand interaction near PNCs. We found an anomalous increase in the lifetime of ligands near PNCs, which agrees remarkably well with experimental data on RAS-RAF kinetics. In particular, analysis of the RAS-RAF data through our model provides falsifiable predictions and novel hypotheses that will not only shed light on the role of RAS-RAF kinetics in various cancers, but also will be useful in studying membrane protein clustering in general. SignificanceSpatial organization of biomolecules shapes the behavior of a cell. It is particularly important during cell-signaling, where transient, dynamic organization of the biomolecules helps cells process signals and respond to them. Nanoclusters of peripheral membrane proteins, such as KRAS, a specific form of dynamic organization of biomolecules, play a critical part in the modulation of cell signals that control various cellular behaviors including cell growth, proliferation, and differentiation. Although we have made significant progress in understanding the structure, size, and origin of the nanoclusters, very little is known about the biophysical processes that control their lifetime. In this paper, we present a mathematical framework that provides quantitative insights into these processes and explains how oncogenic mutations in KRAS may lead to cancers.