Resolving Cadherin Catch Bond Formation at the Single Molecule Level

Abstract

Cadherins are Ca2+-dependent cell-cell adhesion proteins which play key roles in the formation and maintenance of tissues in multi-cellular organisms. We recently showed that cadherins withstand tensile force by forming catch bonds where their bond lifetimes increase with tensile force. Here we resolve the molecular mechanism of cadherin catch bond formation. Using Steered Molecular Dynamics (SMD) simulations, we show that catch bonds are formed because tensile force re-orients the cadherins such that they lock into a tighter contact. Our simulations also predict that cadherins are unable to lock into a tighter binding conformation if their extracellular regions are made more floppy by titrating Ca2+ ions from solution. Using single molecule force measurements with an Atomic Force Microscope (AFM), we confirm that catch bond formation is abolished as Ca2+ concentration is reduced. Based on these results we propose a molecular model by which cadherins withstand mechanical stress and strengthen cell-cell junctions.