Tamara presents Multiscale Models of Integrin-based Mechanosensing

Abstract. Cell-substrate adhesions are specialized regions of the plasma membrane that couple the cytoskeleton network to the extracellular environment. They are critical in several cell activities, including tissue morphogenesis, homeostasis, cell migration and wound healing. Central elements of cell-substrate adhesions are transmembrane receptors, that form physical links between cell cytoskeleton and external binding partners. Integrins are transmembrane receptors that sense, resist and transmit cytoskeletal contractility to the substrate and respond to substrate rigidity via changes in conformation and ligand binding affinity. Integrin resists to contractility and this makes the receptor a cell mechanosensors, responding to mechanical cues with specific kinetic activities. Unfortunately, the biophysical and conformational mechanisms by which adhesions reinforce in response to stress are not fully understood. In this study, we developed a multiscale model of adhesions formation based on coupling Molecular Dynamics, coarse-graining techniques and Brownian Dynamics approaches in order to study mechanisms of adhesion reinforcement. Our model shows that:  integrin activating mutants extend more easily under tension; conformational rearrangements  in proximity of the ligand binding domain of integrin underlie integrin extension; catch-bond kinetics is responsible for integrin-based mechanosensing, leading to enhanced cell spreading and traction stress. These results provide important insights into the biophysical principles and mechanisms of adhesion mechanosensing, with functional consequences on both cell and tissue physiology.