Multiscale model of integrin adhesion assembly

The ability of adherent cells to form adhesions is critical to numerous phases of their physiology. The assembly of adhesions is mediated by several types of integrins. These integrins differ in physical properties, including rate of diffusion on the plasma membrane, rapidity of changing conformation from bent to extended, affinity for extracellular matrix ligands, and lifetimes of their ligand-bound states. However, the way in which nanoscale physical properties of integrins ensure proper adhesion assembly remains elusive. We observe experimentally that both β-1 and β-3 integrins localize in nascent adhesions at the cell leading edge. In order to understand how different nanoscale parameters of β-1 and β-3 integrins mediate proper adhesion assembly, we therefore develop a coarse-grained computational model. Results from the model demonstrate that morphology and distribution of nascent adhesions depend on ligand binding affinity and strength of pairwise interactions. Organization of nascent adhesions depends on the relative amounts of integrins with different bond kinetics. Moreover, the model shows that the architecture of an actin filament network does not perturb the total amount of integrin clustering and ligand binding; however, only bundled actin architectures favor adhesion stability and ultimately maturation. Together, our results support the view that cells can finely tune the expression of different integrin types to determine both structural and dynamic properties of adhesions.
Author summary Integrin-mediated cell adhesions to the extracellular environment contribute to various cell activities and provide cells with vital environmental cues. Cell adhesions are complex structures that emerge from a number of molecular and macromolecular interactions between integrins and cytoplasmic proteins, between integrins and extracellular ligands, and between integrins themselves. How the combination of these interactions regulate adhesions formation remains poorly understood because of limitations in experimental approaches and numerical methods. Here, we develop a multiscale model of adhesion assembly that treats individual integrins and elements from both the cytoplasm and the extracellular environment as single coarse-grained (CG) point particles, thus simplifying the description of the main macromolecular components of adhesions. The CG model implements sequential interactions and dependencies between the components and ultimately allows one to characterize various regimes of adhesions formation based on experimentally detected parameters. The results reconcile a number of independent experimental observations and provide important insights into the molecular basis of adhesion assembly from various integrin types.