Force regulated conformational change of integrin αVβ3

Matrix Biol. 2017 Jul;60-61:70-85. doi: 10.1016/j.matbio.2016.07.002. Epub 2016 Jul 14.

Abstract

Integrins mediate cell adhesion to extracellular matrix and transduce signals bidirectionally across the membrane. Integrin αVβ3 has been shown to play an essential role in tumor metastasis, angiogenesis, hemostasis and phagocytosis. Integrins can take several conformations, including the bent and extended conformations of the ectodomain, which regulate integrin functions. Using a biomembrane force probe, we characterized the bending and unbending conformational changes of single αVβ3 integrins on living cell surfaces in real-time. We measured the probabilities of conformational changes, rates and speeds of conformational transitions, and the dynamic equilibrium between the two conformations, which were regulated by tensile force, dependent on the ligand, and altered by point mutations. These findings provide insights into how αVβ3 acts as a molecular machine and how its physiological function and molecular structure are coupled at the single-molecule level.

Keywords: Binding kinetics; Biomechanics; Force regulation; Integrin conformational change; Integrin α(V)β(3).

Publication types

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

MeSH terms

  • Animals
  • Biomechanical Phenomena
  • Biotinylation
  • Cell Adhesion
  • Cell Line
  • Endothelial Cells / metabolism*
  • Endothelial Cells / ultrastructure
  • Erythrocytes / chemistry
  • Extracellular Matrix / chemistry*
  • Extracellular Matrix / metabolism
  • Extracellular Matrix / ultrastructure
  • Fibronectins / chemistry*
  • Gene Expression
  • Glass / chemistry
  • Humans
  • Integrin alphaVbeta3 / chemistry*
  • Integrin alphaVbeta3 / genetics
  • Integrin alphaVbeta3 / metabolism
  • Kinetics
  • Lung / cytology
  • Lung / metabolism
  • Mice
  • Molecular Probes / chemistry
  • Point Mutation
  • Protein Binding
  • Protein Conformation
  • Signal Transduction
  • Single Molecule Imaging / methods

Substances

  • Fibronectins
  • Integrin alphaVbeta3
  • Molecular Probes
  • fibronectin type III like peptide, human