Nanoscale protein clustering modulates the input-output response of cellular signalling pathways

Abstract

A key function of the plasma membrane is regulating signal transduction. Proteins involved in the transduction process play a signal-processing role; mapping an input (e.g. number of engaged receptors) to an output (e.g. level of downstream phosphorylation). In many cases, a digital mapping is desirable, i.e. that a cell activates or responds fully once a set input threshold is surpassed. It is believed that the nanoscale organisation of proteins, such as their clustering, modulates this behaviour by altering the frequency of protein-protein interactions. Here, we develop a generalised simulator for dynamic molecular clustering built around agent-based modelling. We show that the clustering properties (e.g. size of clusters, percentage of monomers) tunes the cellular response. This work paves the way for designing potential therapeutic interventions that alter the nanoscale patterning of molecules on the cell surface in order to alter cell behaviour. AUTHOR SUMMARYSignal transduction is the process by which cells convert external signals into internal responses. This is essential for such functions as hormone signalling and immunity. Many membrane proteins form nanoscale clusters on the cell surface, and state-of-the-art imaging methods allow us to see these clusters in detail. We developed an agent-based simulator to explore how clustering of key signaling proteins (such as kinases and phosphatases) can influence cell signalling outputs. Our results suggest that protein clustering can "digitize" signals, pushing cells to respond in an "all-or-nothing" manner, rather than producing a smooth range of responses. This research contributes to a broader understanding of how dynamic reorganization of transmembrane proteins contributes to information processing. This is a central question in systems biology, with relevance to the fields of immunology, neuroscience, and cancer. By highlighting how the geometric properties of protein distributions can alter signalling responses, we may identify novel methods to manipulate cell behavior.