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

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