Simulating Mono-and Multi-Protein Phosphorylation within Nanoclusters

Protein nanoclustering is a characteristic feature of their activated state and is essential for forming numerous subcellular structures. The formation of these nanoclusters is highly dependent on a series of post-translational modifications, such as mono-and multi-phosphorylation and dephosphorylation of residues. We theoretically simulate how a protein can be either mono-or multi-phosphorylated on several residues in functional nanoclusters, depending on effective biophysical parameters (diffusion, dwell time, etc.). Moving beyond a binary view of phosphorylation, this approach highlights the interplay between mono-and multi-phosphorylation, the cooperative effects generally associated with multi-phosphorylation networks, and stresses the role of phosphatases in transforming graded phosphorylation signals into almost switch-like responses. The results are discussed in light of experiments that probe the distribution of phospho-residues.