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The Molecular Mechanics of Hearing and Deafness

Our senses are essential for survival and for the exploration of natural environments, and much has been learned about the molecular basis of vision, olfaction, and taste. Yet only a few of the molecules mediating touch and sound perception have been discovered.

Now, researchers from Harvard University have resolved the molecular structure of one key protein important for sound perception. They used this structure, together with molecular dynamics simulations, to understand the protein’s mechanics and function in hearing and deafness.

Hair cells of the inner ear are exquisite mechanoreceptors: minute motion of their apical hair bundles by sound becomes an electrical signal that is then transmitted to the brain. At the core of this mechanotransduction process there is a fine filament — termed the “tip link” — that pulls open force-gated ion channels, thereby causing depolarization. This tip link filament is made of two atypical cadherins, cadherin-23 and protocadherin-15. Mutation of either causes hereditary deafness.

To elucidate the function of these proteins, the researchers determined the x-ray crystal structure of cadherin-23's N-terminal end at the Advanced Photon Source at Argonne National Laboratory and NSLS. The structure revealed a novel calcium binding site that defines a subfamily of cadherin adhesion molecules.

Classical cadherins, the calcium-dependent "glue" that keeps cells together in multicellular organisms, use a "strand-exchanged" mechanism to form adhesive bonds. However, the new structure suggests that cadherin-23 must use a different mechanism, perhaps through a calcium bridge, with calcium ions participating in the interface between cadherin-23 and protocadherin-15.

With the cadherin-23 structure in hand, the team used molecular dynamics simulations to determine its elasticity. The tip link has been assumed to be a relatively elastic, spring-like molecule. However, an extensive set of atomistic simulations revealed a stiff cadherin-23 molecule, with tightly-bound calcium ions preventing mechanical unfolding.

Structural information on wild-type and mutant cadherin-23 proteins can help pinpoint the mechanisms by which mutations cause disease. The team used the determined crystal structure of cadherin-23 carrying a mutation known to cause deafness in humans. Biochemical assays demonstrated that this mutation impairs calcium binding, and simulations showed that in the absence of bound calcium, cadherin-23 becomes a mechanically weak protein. The mutation-induced weakening of cadherin-23 suggests that mutant tip links are more prone to mechanical failure, causing hearing loss.

— David Corey and Rachelle Gaudet, Harvard University

M. Sotomayor, W.A. Weihofen, R. Gaudet, D.P. Corey, “Structural Determinants of Cadherin-23 Function in Hearing and Deafness,” Neuron, 66(1), 85, (2010).

A close-up view of the linker region between cadherin-23 repeats 1 and 2 is shown while the protein is stretched from both ends. The simulation mimics in vivo conditions in which tip-link cadherins are stretched during sound mechanotransduction at hair cells of the inner ear. Calcium ions (shown as green spheres) were found to be essential for the mechanical stability of the protein (shown in cartoon and sticks).

Click here to see simulation movie.

Figure 1