Structure of a Force-Conveying Cadherin Bond Essential for Inner-Ear Mechanotransduction

Hearing and balance use hair cells in the inner ear to transform mechanical stimuli into electrical signals(1). Mechanical force from sound waves or head movements is conveyed to hair-cell transduction channels by tip links(2,3), fine filaments formed by two atypical cadherins: protocadherin-15 and cadherin-23(4,5). These two proteins are products of deafness genes(6–10) and feature long extracellular domains that interact tip-to-tip(5,11) in a Ca(2+)-dependent manner. However, the molecular architecture of the complex is unknown. Here we combine crystallography, molecular dynamics simulations, and binding experiments to characterize the cadherin-23 and protocadherin-15 bond. We find a unique cadherin interaction mechanism, with the two most N-terminal cadherin repeats (EC1+2) of each protein interacting to form an overlapped, antiparallel heterodimer. Simulations predict that this tip-link bond is mechanically strong enough to resist forces in hair cells. In addition, the complex becomes unstable upon Ca(2+) removal due to increased flexure of Ca(2+)-free cadherin repeats. Finally, we use structures and biochemical measurements to understand molecular mechanisms by which deafness mutations disrupt tip-link function. Overall, our results shed light on the molecular mechanics of hair-cell sensory transduction and on new interaction mechanisms for cadherins, a large protein family implicated in tissue and organ morphogenesis(12,13), neural connectivity(14), and cancer(15).