Beyond Cell–Cell Adhesion: Sensational Cadherins for Hearing and Balance

Cadherins form a large family of proteins often involved in calcium-dependent cellular adhesion. Although classical members of the family can provide a physical bond between cells, a subset of special cadherins use their extracellular domains to interlink apical specializations of single epithelial sensory cells. Two of these cadherins, cadherin-23 (CDH23) and protocadherin-15 (PCDH15), form extracellular "tip link" filaments that connect apical bundles of stereocilia on hair cells essential for inner-ear mechanotransduction. As these bundles deflect in response to mechanical stimuli from sound or head movements, tip links gate hair-cell mechanosensitive channels to initiate sensory perception. Here, we review the unusual and diverse structural properties of these tip-link cadherins and the functional significance of their deafness-related missense mutations. Based on the structural features of CDH23 and PCDH15, we discuss the elasticity of tip links and models that bridge the gap between the nanomechanics of cadherins and the micromechanics of hair-cell bundles during inner-ear mechanotransduction.