The stereocilia bundle present at the apical surface of inner ear hair cells is the only device that can convert mechanical vibrations in inner ear into neural signals in the human auditory system. Maintenance of the unique morphology and proper functions of stereocilia bundle require collaborations of multiple proteins, of which mutations could cause deafness. Usher syndrome is the most frequently identified hereditary deaf-blindness. Among three clinical subtypes (I, II, and III), Usher syndrome I (USH1) is the most severe form. Five genes have been identified as USH1 genes which encode cadherin23, protocadherin15, harmonin, sans, and myosin VIIa. Mutations of any one of these genes have been found to lead to severe morphological defects of stereocilia bundles of hair cells. Therefore...[ Read more ]

The stereocilia bundle present at the apical surface of inner ear hair cells is the only device that can convert mechanical vibrations in inner ear into neural signals in the human auditory system. Maintenance of the unique morphology and proper functions of stereocilia bundle require collaborations of multiple proteins, of which mutations could cause deafness. Usher syndrome is the most frequently identified hereditary deaf-blindness. Among three clinical subtypes (I, II, and III), Usher syndrome I (USH1) is the most severe form. Five genes have been identified as USH1 genes which encode cadherin23, protocadherin15, harmonin, sans, and myosin VIIa. Mutations of any one of these genes have been found to lead to severe morphological defects of stereocilia bundles of hair cells. Therefore, how these USH1 proteins collaborate and participate in stereocilia bundle development is the key question for understanding both the stereocilia bundle development and the etiology of Usher syndrome I.

In collaboration with my lab mates, we systematically characterized the interaction network of four USH1 proteins, namely cadherin23, harmonin, sans and myosin VIIa. We have determined a series of USH1 protein complex structures to elucidate the detailed molecular mechanisms governing this interaction network. Together with biochemical studies presented in this thesis, we reveal the molecular mechanisms underlying two important cellular processes for the stereocilia bundle development and function. First, the cadherin23/harmonin interaction, which is responsible for anchoring tip link to actin filaments, forms a large protein complex assembly that may function to offer tip link a strong root to resist the mechanical force generated by sound waves. Second, we discovered that sans acts as an adaptor for harmonin to be loaded onto myosin VIIa for transport to stereocilia. Finally, the MyTH4-FERM-SH3 structure of myosin VIIa gives a molecular-based explanation for 19 missense disease-causing mutations identified within this region.