Nanomechanics of tip-link cadherins

Hearing and balance rely on the transduction of mechanical stimuli arising from sound waves or head movements into electrochemical signals. This archetypal mechanoelectrical transduction process occurs in the hair-cell stereocilia of the inner ear, which experience continuous oscillations driven by undulations in the endolymph in which they are immersed. The filamentous structures called tip links, formed by an intertwined thread composed of an heterotypic complex of cadherin 23 and protocadherin 15 ectodomain dimers, connect each stereocilium to the tip of the lower sterocilium, and must maintain their integrity against continuous stimulatory deflections. By using single molecule force spectroscopy, here we demonstrate that in contrast to the case of classical cadherins, tip-link cadherins are mechanoresilient structures even at the exceptionally low Ca 2+ concentration of the endolymph. We also show that the D101G deafness point mutation in cadherin 23, which affects a Ca 2+ coordination site, exhibits an altered mechanical phenotype at the physiological Ca 2+ concentration. Our results show a remarkable case of functional adaptation of a protein’s nanomechanics to extremely low Ca 2+ concentrations and pave the way to a full understanding of the mechanotransduction mechanism mediated by auditory cadherins.