Extracellular pH and Regulation of Integrin Activation

Abstract

It is well established that chemomechanical properties of the extracellular matrix (ECM) can have a profound effect on cell processes such as adhesion, migration, and differentiation. To understand and modulate such complex processes, it is crucial to have a detailed understanding of the feedback between a cell and the adjacent microenvironment. This is particularly important in the tumor and wound environments, where the ECM often exhibits altered characteristics such as acidic extracellular pH. This microenvironmental property could significantly alter the interactions between cell surface integrin receptors and ECM ligands, which are critical to downstream cell behaviors such as adhesion, migration, and signaling. Here, we use molecular dynamics simulations to examine the role of acidic extracellular pH in regulating integrin activation. The simulation system is the headpiece domains of integrin αvβ3 in complex with a cyclic RGD peptide. Multi Conformation Continuum Electrostatics was used to predict pKa values for all titratable residues in the system, and results were used to select residues for protonation in order to represent an effective acidic extracellular pH. Molecular dynamics simulations at acidic and physiological pH were compared to examine the effect of pH on αvβ3-RGD conformational states. Our results suggest that acidic pH promotes integrin headpiece opening, which is one of the steps in integrin activation, and we propose a possible mechanism for this effect. This finding is consistent with experimental data from the literature, and has important implications for cell adhesion and migration in cancer and wound healing.