The role of membrane protein spatial arrangements in cellular signaling: A theoretical study.

Abstract

Mechanistic models of reaction and diffusion of membrane proteins area valuable tool to gain insight into signaling. The collision coupling model describes the interaction of receptors on the membrane and requires they are within physical proximity to react, and hence the spatial location of membrane proteins plays an important role in signaling. This work is divided into three areas focusing on receptor crosstalk, the movement of ligand among receptors, and integrin binding for cell adhesion. First, a variety of experimental data on G-protein activation have been interpreted as suggesting (or not) that receptor crosstalk is regulated by the compartmentalization of receptors and/or G-proteins in addition to a collision coupling mechanism. Mathematical models of G-protein activation via collision coupling but without compartmentalization are used to demonstrate that these disparate observations do not imply the existence of such compartments. Second, I examined the competition of agonist and antagonist for binding to receptors. This is applicable to drug discovery as many therapeutic situations as it is common for an endogenous agonist to be present along with the therapeutic agent (e.g. schizophrenia, hypertension and others). When comparing cases of equal occupancy of receptors by agonist, the antagonist dissociation rate constant had the unexpected effect of modulating G-protein activation and partially decoupling G-protein activation from receptor phosphorylation. Monte Carlo simulations were used to scan a broad range of conditions and to identify regimes that may be of interest experimentally. Third, cell adhesion requires both integrin occupancy and integrin clustering. A Monte Carlo model of the cell-substrate interface demonstrated that ligand organization or integrin dimerization alone are unable to increase the number of bound integrins, but when both are present they cooperate to increase both binding and clustering of integrins. These results describe a potential mechanism for the clustering of integrin receptors and avidity modulation and for the design of surfaces for tissue engineering to manipulate cell adhesion. Overall, this work provides us with a more mechanistic understanding of signaling and cellular response.