Dimerization-based control of cooperativity

Abstract

Cooperativity of ligand-receptor binding influences the input-output behavior of a biochemical system and thus is an important determinant of its physiological function. Canonically, such cooperativity is understood in terms of ligand-receptor binding affinity, where an initial binding event changes the affinity for subsequent binding events. Here, we demonstrate that dimerization—a simple yet pervasive signaling motif across biology—can have significant control over cooperativity and even dominate over the canonical mechanism. Through an exhaustive parameter sensitivity analysis of a general kinetic model for signal-mediated dimerization, we show that quantitative modulation of dimerization processes can reinforce, eliminate, and even reverse cooperativity imposed by the canonical allosteric ligand-receptor binding affinity mechanism. The favored accumulation of stoichiometrically asymmetric dimers (those with ligand-receptor stoichiometry of 1:2) is a major determinant of dimerization-based cooperativity control. However, simulations demonstrate that favoring accumulation of such stoichiometrically asymmetric dimers can either increase or decrease cooperativity, and thus the quantitative relationship between stoichiometrically asymmetric dimers and cooperativity is highly dependent on the parameter values of the particular system of interest. These results suggest that the dimerization motif provides a novel mechanism for both generating and quantitatively tuning cooperativity that, due to the ubiquity of dimerization motifs in biochemical systems, may play a major role in a host of biological functions. Thus, the canonical, allosteric view of cooperativity is incomplete without considering dimerization effects, which is of particular importance as dimerization is often a necessary feature of the allosteric mechanism.

A mechanistic pan-cancer pathway model informed by multi-omics data interprets stochastic cell fate responses to drugs and mitogens

“…The receptor tyrosine kinase (RTK) submodel, inspired by several prior models [ 22 , 23 ], depicts ligand-binding and dimerization reactions for many receptors that are frequently overexpressed, mutated or implicated in cancer, including the ErbB family (HER1-4), the hepatocyte growth factor receptor (cMet), the platelet-derived growth factor receptor (PDGFR), the fibroblast growth factor receptor (FGFR), the insulin-like growth factor receptor (IGFR), and the insulin receptor (INSR). Ligand stimulation, for most receptors, induces receptor dimerization and phosphorylation of intracellular tyrosine residues, which recruits adaptor proteins (Grb2/SOS, PI3K, and PLCγ) to mediate downstream signaling (see S1 Supplemental Methods for more details and S2 Table for rate laws and constants).…”

Modelling co-translational dimerisation for programmable nonlinearity in synthetic biology

“…of the cell are still based on unclear dynamics. Here, we focus on modelling protein dimerisation [33] within regulatory interactions, as a way predict and rationally design nonlinearity.…”

“…There is one such processes, that, despite being of fundamental importance for genetic circuits and biological computation, has received relatively little attention to this end: the mechanistic understanding of nonlinear dynamics [29,30,31,32]. Specifically, due to its relevance for genetic circuits, the nonlinearity that emerges from the dimerisation of regulatory proteins [33]. Upon gene expression, most resulting proteins are monomers that need to interact to form dimers (or higher-order oligomers); it is only the protein in its final from that is active.…”

A yeast surface display platform for plant hormone receptors: Toward directed evolution of new biosensors

“…At high local concentrations on the surface of yeast, dimerization of PYR1 could strongly compete with ABA and ΔN‐HAB1 binding. If the PYR1–ABA/PYR1 dimer is more stable than the PYR1/PYR1 or PYR1–ABA/PYR1–ABA dimers, negative cooperativity is particularly likely . It is known that the H60P mutation disrupts the formation of PYR1/PYR1 dimers, while the six mutations in PYR1 MANDI could have decreased or eliminated its dimerization potential.…”