Abstract
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 Ca2+ concentration of the endolymph. We also show that the D101G deafness point mutation in cadherin 23, which affects a Ca2+ coordination site, exhibits an altered mechanical phenotype at the physiological Ca2+ concentration. Our results show a remarkable case of functional adaptation of a protein’s nanomechanics to extremely low Ca2+ concentrations and pave the way to a full understanding of the mechanotransduction mechanism mediated by auditory cadherins.
Highlights
Hearing and balance perception in vertebrates is considered as one of the most evident mechanotransduction processes[1]
This additional resistance element to mechanical unfolding known as the calcium rivet, which is present in classical cadherins upon Ca2+ coordination, ensures that the extracellular cadherin (EC) domain remains folded when subjected to low range forces[17]
The calcium rivets observed for cadherin 23 (CDH23) are more obvious than those shown by classical cadherins
Summary
Hearing and balance perception in vertebrates is considered as one of the most evident mechanotransduction processes[1]. Among other connectors between the stereocilia, the so-called tip-link, a long intertwined filament formed by a helical dimer of cadherin 23 (CDH23) in the apical end bound head-to-head to a helical dimer of protocadherin 15 (PCDH15) in the basal end, is relevant for the proper gating process and coupling of the MET response[2,4,5,6,7]. Both CDH23 and PCDH15 belong to the Cadherin Superfamily, a large Ca2+-binding protein family responsible for cell-cell adhesion[11]. Our data provide a necessary molecular insight into this important mechanotransduction system, setting the limits of its proper mechanical response
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