Multiscale model of integrin adhesion assembly

PLoS Comput Biol. 2019 Jun 4;15(6):e1007077. doi: 10.1371/journal.pcbi.1007077. eCollection 2019 Jun.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Adhesion / physiology*
  • Cell Membrane / chemistry
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Computational Biology
  • Extracellular Matrix / chemistry
  • Extracellular Matrix / metabolism
  • Fibroblasts / cytology
  • Humans
  • Integrins* / chemistry
  • Integrins* / metabolism
  • Integrins* / physiology
  • Kinetics
  • Models, Biological*
  • Molecular Dynamics Simulation

Substances

  • Integrins

Grant support

This research was supported by the Department of Defense Army Research Office through MURI grant W911NF1410403. It was also partially supported by the University Chicago Materials Research Science and Engineering Centre, which is funded by the National Science Foundation under award number DMR-1420709. Computer time was provided by the University of Utah Research Computing Centre. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.