Bidirectional Allostery Mechanism in Catch-Bond Formation of CD44 Mediated Cell Adhesion

J Phys Chem Lett. 2024 Oct 31;15(43):10786-10794. doi: 10.1021/acs.jpclett.4c02598. Epub 2024 Oct 21.

Abstract

Catch-bonds, whereby noncovalent ligand-receptor interactions are counterintuitively reinforced by tensile forces, play a major role in cell adhesion under mechanical stress. A basic prerequisite for catch-bond formation, as implicated in classic catch-bond models, is that force-induced remodeling of the ligand binding interface occurs prior to bond rupture. However, what strategy receptor proteins utilize to meet such specific kinetic control remains elusive. Here we report a bidirectional allostery mechanism of catch-bond formation based on theoretical and molecular dynamics simulation studies. Binding of ligand allosterically reduces the threshold force for unlocking of otherwise stably folded force-sensing element (i.e., forward allostery), so that a much smaller tensile force can trigger the conformational switching of receptor protein to high binding-strength state via backward allosteric coupling before bond rupture. Such bidirectional allostery fulfills the specific kinetic control required by catch-bond formation and is likely to be commonly utilized in cell adhesion. The essential thermodynamic and kinetic features of receptor proteins essential for catch-bond formation were identified.

MeSH terms

  • Allosteric Regulation
  • Cell Adhesion*
  • Humans
  • Hyaluronan Receptors* / chemistry
  • Hyaluronan Receptors* / metabolism
  • Kinetics
  • Ligands
  • Molecular Dynamics Simulation
  • Protein Binding
  • Thermodynamics

Substances

  • Hyaluronan Receptors
  • Ligands