Allovalency revisited: An analysis of multisite phosphorylation and substrate rebinding

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 dissociation, a ligand immediately rebinds to its receptor. How such effects may influence cell signaling systems is not well understood. 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 generate a highly cooperative biological response.

Integrating multiple experimental data to determine conformational ensembles of an intrinsically disordered protein

“…Low internal friction and fast chain reconfigurations are therefore expected for short-to-intermediate separations. In a kinetic model of ultrasensitive binding, fast reconfiguration dynamics provides more opportunities for unbound CPDs to (re)bind before pSic1 diffuses out of proximity of Cdc4 [20,21,23]. In the polyelectrostatic model, fast reconfiguration dynamics facilitates pSic1's dynamic interactions with Cdc4 through electrostatic averaging effects [22,25].…”

“…Different biophysical models have been proposed to explain the ultrasensitive dependence of the Sic1-Cdc4 interaction on the number of phosphorylated CPDs. A kinetic model argued that the probability of Sic1 rebinding before diffusive exit could exhibit an ultrasensitive dependence on the number of phosphorylated CPDs, dependent on the timescales of diffusion and chain dynamics [20,21]. A polyelectrostatic model suggested that long-range electrostatic interactions between the positively charged CPD binding pocket on Cdc4 and the constellation of unbound negatively charged phosphorylated CPDs on Sic1 could yield ultrasensitive binding [22,23].…”

Behaviour of intrinsically disordered proteins in protein–protein complexes with an emphasis on fuzziness

“…1c. The concept was developed by Klein, Pawson and Tyers in 2003 [22] and discussed and elaborated by others [23, 29]. The identical binding sites on the ligand compete for a single binding site on the receptor and only one binding site on the ligand can bind at any given time [22], which is nicely exemplified by multiple phosphorylations on an IDP binding to and competing for the same site [30].…”

“…Please note, that the allovalency model has been discussed and expanded beyond the present formulation by Locasale [29]. …”

A high-throughput screen for transcription activation domains reveals their sequence characteristics and permits reliable prediction by deep learning

“…This feature is found in both natural and synthetic ADs and seems a general feature corresponding to function. We suggest that these clusters function to increase the effective affinity of the AD peptides for their coactivator targets using a mechanism similar to avidity or allovalency -whereby a receptor dynamically interacts with multiple binding sites on a single ligand, effectively inhibiting the dissociation of the two molecules (Locasale, 2008;Olsen et al, 2017). This mechanism fits nicely with the dynamic and fuzzy binding of acidic activators to Med15, and presumably other coactivator targets, as well as the finding that ADcoactivator binding is driven in part by a favorable entropy change Tuttle et al, 2018).…”