Sensorineural hearing loss (SNHL) is the most common sensory defect in the world affecting about 1 in every 500 children as well as a large proportion of the ageing population. Usher Syndrome, a form of deaf-blindness, is a genetic disease often caused by mutations in genes encoding proteins that are expressed in the mechanically sensitive stereocilia of hair cells in the inner ear. Mutations in one such gene, Cadherin 23 (Cdh23), has been linked to a subtype of Usher Syndrome, USH1D. Cadherin 23 is a component of the tip-link complex, which is thought to be important for force transmission onto mechanically gated ion channels in hair cells. CDH23 differs from classical cadherins in that it contains more than 5 extracellular cadherin (EC) repeats and forms extensive lateral contacts along the length of the CDH23 extracellular domain. It also binds in trans to PCDH15, to form tip links. However, the mode in which CDH23 adheres to PCDH15 is unknown. Structural analysis of CDH23 is anticipated to shed light on the binding mechanism. I therefore solved the structure of the N-terminus of CDH23, which binds to PCDH15, at a resolution of 1.1 Angstrom. Unlike classical cadherins, CDH23 has a polar extension that binds calcium. Mutations in these residues affect interaction between CDH23 and PCDH15, suggesting a new mode of protein-protein interaction not used by classical cadherins.
