Allovalency revisited: an analysis of multisite phosphorylation and substrate rebinding

TL;DR

This paper investigates how multisite phosphorylation and ligand rebinding influence cell signaling, using a formalism and simulations to reveal different regimes and the limited role of rebinding in generating high cooperativity.

Contribution

It introduces a self-consistent integral equation formalism combined with Monte Carlo simulations to analyze multisite phosphorylation effects on ligand rebinding in cell signaling.

Findings

Multiple regimes of rebinding effects are identified.

Ligand rebinding can nonlinearly influence dose response curves.

Rebinding alone is insufficient to produce highly cooperative responses.

Abstract

The utilization of multiple phosphorylation sites in regulating a biological response is ubiquitous in cell signaling. If each site contributes an additional, equivalent binding site, then one consequence of an increase in the number of phosphorylations may be to increase the probability that, upon disassociation, a ligand immediately rebinds to its receptor. How such effects may influence cell signaling systems has been less studied. Here, a self-consistent integral equation formalism for ligand rebinding, in conjunction with Monte Carlo simulations, is employed to further investigate the effects of multiple, equivalent binding sites on shaping biological responses. Multiple regimes that characterize qualitatively different physics due to the differential prevalence of rebinding effects are predicted. Calculations suggest that when ligand rebinding contributes significantly to the dose response, a purely allovalent model can influence the binding curves nonlinearly. The model also predicts that ligand rebinding in itself appears insufficient to generative a highly cooperative biological response.