Structural Determinants of Protocadherin-15 Function in Inner-Ear Mechanotransduction

Cadherins form a large superfamily of proteins essential for morphogenesis, neuronal connectivity, and tissue integrity. Two atypical members of this superfamily, cadherin-23 (cdh23) and protocadherin-15 (pcdh15), are also involved in hereditary deafness and blindness. In the inner ear, these two proteins interact to form the tip link, a fine filament that pulls open transduction channels to initiate a cascade of events leading to sensory perception. Here, we present structural, computational, and biophysical experiments that reveal unique properties of the tip link's extracellular cadherin (EC) repeats. Our crystal structures, simulations, and binding assays show how the N-terminus of pcdh15 and several of its variants form a mechanically strong and calcium-dependent heterophilic complex with the N-terminus of cdh23. In addition, structures and simulations of other domains of pcdh15 including EC2-3, EC7-8 and EC8-10, reveal unusual inter-repeat linker regions that alter the tertiary structure and elasticity of pcdh15. Overall, our results provide a molecular view of tip link mechanics and identify the structural determinants of pcdh15 function in vertebrate mechanosensation.