Research Summary

Deciphering the mechano-responsive behavior of cadherins in hearing

Hearing is one of the most complicated but well developed sensing ability of mammals. In hearing, sound wave deflects the hair cells in inner ear. The precise deflection of hair cells leads to the opening of ion-channels and generates electrical signal that is carried by neurons to brain. Brain decodes the electrical signal as sound. As expected, these hair cells deflect thousands of times in a second during a stimulation. More importantly, the hair cells in accord with their load-bearing molecular springs restore their structural and functional integrity after each stimulation for retaining sensitivity to next transient stimuli. The correlation between molecular springs and hearing is further reinforced with the fact that mutational modification on these springs directly associated with hearing impairment diseases like Usher Syndrome. Molecular springs that act together to adaptively convert the sound pressure into hearing are identified, however, little is known about the molecular elasticity of these load-bearing molecular springs and their precise and repetitive response to force. The overarching goals of this proposal are therefore to decipher the force-regulated molecular elasticity of the springs, and resolve how mutations tune the mechano-responsive properties of such springs leading to deafness. We propose single molecule force spectroscopy based experiments using AFM, single molecule FRET along with in-silico Molecular Dynamics and Steered Molecular Dynamics simulations to achieve the proposed goals. 

                                          

Figure Legend: : Fig 1. (a). Single molecule Force Spectroscopy to measure the interactions of cadherins in tip-links under tension and (b). Single-pair FRET to decipher the domains involved In tip-link formation.