Knowledge Bank

Every day we accrue an exceptional amount of information from our environment. We utilize this sensory information to guide us as we make decisions for our survival. Most animals gather this information through taste, sight, smell, touch, and auditory cues. Each of these sensory mechanisms involve quite intricate and complex systems which have been optimally tuned to suit the needs of the species in its environment. The process of auditory transduction is made possible by special- ized cells, known as hair cells, found in the Organ of Corti inside of the ear. By delineating the molecular mechanisms involved in hair cell function, we aim to better understand the root causes of hearing loss and deafness.

Hair cells are responsible for mediating auditory perception in the cochlea of the inner ear. They can accomplish this through hair-cell mechanotransduction, a process by which a complex of ion channels and other accessory proteins convert mechanical stimuli from sound and head movement into the language of the brain: electrochemical signals. These hair cells possess bundles of hair- like protrusions known as stereocilia that are arranged in rows of increasing height, similar to a staircase arrangement. Tip links, which are proteinaceous filaments composed of protocadherin-15 (PCDH15) and cadherin-23 (CDH25), link the tip of one stereocilia to the side of its taller neighbor. Sound waves deflect these hair bundles which induces a tension in the tip links. These tip links mechanically activate an ion channel complex, which is believed to be formed by accessory proteins and a membrane protein known as TMC1 that facilitates the influx of ions that depolarizes the hair cells during auditory transduction.

A detailed view of a protein's structure is exceedingly useful to describe the functional role of the protein. Unfortunately, structural studies of proteins are often exceptionally challenging to per- form, and experimental structures of TMC1 have remained elusive. Interestingly, recent biochemical and bioinformatics evidence suggests that the TMC family of proteins are distant homologs of both the TMEM16s and OSCA families of proteins for which experimental structures have recently been determined. These structures present a unique opportunity to develop structure-based homology models of TMC1, which can be used in molecular dynamics (MD) simulations in order to determine an in-silico conductance for the putative ion channel. These novel simulations have revealed that TMC1 can conduct ions at a rate comparable to that of the native mechanotransduction channel, thus solidifying its role as the putative pore of the mechanotransduction apparatus.

Biochemical experiments have shown that TMC1 and at least three additional membrane proteins are part of the apparatus. These proteins include PCDH15, the tetraspan membrane protein of hair- cell stereocilia (TMHS), and the transmembrane inner-ear expressed protein (TMIE). Additional simulations are being conducted to determine the role of these proteins in the activation of the mechanotransduction apparatus. A current working theory is that PCDH15, in combination with TMHS, relays the mechanical tension to the lipid membrane, which in turn pulls on TMC1 and mechanically opens its pore. Steered MD simulations are being conducted to quantify the role of PCDH15 and TMHS in this process, and results may suggest the potential gating mechanism for the transduction channel. The combined studies of this project delineate the role of several proteins involved in inner-ear mechanotransduction and provide further details on the molecular basis of sensory auditory transduction.