Abstract
Hair-cell tip links are fine filaments that directly convey mechanical force to inner ear mechanotransduction channels. These filaments are made of protocadherin-15 (PCDH15) and cadherin-23 (CDH23), two deafness-related proteins that feature long extracellular domains interacting tip-to-tip in a calcium dependent manner. Here we combine X-ray crystallography, molecular dynamics simulations, and binding experiments to explore the molecular mechanisms by which deafness mutations disrupt tip-link function in hair-cell mechanotransduction. We find that these mutations disrupt tip links through impaired interaction between PCDH15 and CDH23 (PCDH15-R113G and PCDH15-I108N), impaired calcium binding (CDH23-D1010G), subtle weakening of structural stability (CDH23-S47P), or impaired folding (PCDH15-D157G). Interestingly, the biochemical effects of each of these deafness mutations correlate with the severity of the reported inner-ear phenotype. Our results shed light on the molecular mechanisms of hair-cell sensory transduction and may help develop tailored treatments for cadherin-mediated deafness.
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