Cardiac desmosomal adhesion relies on ideal-, slip- and catch bonds

The cardiac muscle consists of individual cardiomyocytes that are mechanically linked by desmosomes. Desmosomal adhesion is mediated by densely packed and organized cadherins which, in presence of Ca²⁺, stretch out their extracellular domains (EC) and dimerize with opposing binding partners by exchanging an N-terminal tryptophan. The strand-swap binding motif of cardiac cadherins like desmocollin 2 (Dsc2) (and desmoglein2 alike) is highly specific but of low affinity with average bond lifetimes in the range of approximately 0.3 s. Notably, despite this comparatively weak interaction, desmosomes mediate a stable, tensile-resistant bond. In addition, force mediated dissociation of strand-swap dimers exhibit a reduced bond lifetime as external forces increase (slip bond). Using atomic force microscopy based single molecule force spectroscopy (AFM-SMFS), we demonstrate that Dsc2 has two further binding modes that, in addition to strand-swap dimers, most likely play a significant role in the integrity of the cardiac muscle. At short interaction times, the Dsc2 monomers associate only loosely, as can be seen from short-lived force-independent bonds. These ideal bonds are a precursor state and probably stabilize the formation of the self-inhibiting strand-swap dimer. The addition of tryptophan in the measurement buffer acts as a competitive inhibitor, preventing the N-terminal strand exchange. Here, Dsc2 dimerizes as X-dimer which clearly shows a tri-phasic slip-catch-slip type of dissociation. Within the force-mediated transition (catch) regime, Dsc2 dimers switch between a rather brittle low force and a strengthened high force adhesion state. As a result, we can assume that desmosomal adhesion is mediated not only by strand-swap dimers (slip) but also by their precursor states (ideal bond) and force-activated X-dimers (catch bond).