Abstract
Our senses of touch, hearing, balance, and proprioception depend on mechanically gated ion channels, which transduce mechanical energy into electrical signals that are transmitted to the brain. Previous studies on the mechanisms of hearing have elucidated the biophysical properties of the mechanotransduction (MET) channel essential for hearing, yet its molecular identity and structure remain elusive. The trantasmembrane channel-like 1 protein (TMC1) localizes to the site of the MET channel, interacts with the tip-link responsible for mechanical gating, and genetic alterations in TMC1 alter MET channel properties and cause deafness, supporting the hypothesis that TMC1 forms the MET channel. We generated a model of TMC1 based on X-ray and cryo-EM structures of TMEM16 proteins, revealing the presence of a large cavity near the protein-lipid interface that also harbors two TMC1 mutations (hTMC1 p.M418K and p.D572N/H) that cause autosomal dominant hearing loss, suggesting that it could function as a permeation pathway. We also find that hair cells are permeable to 3 kDa dextran labeled with Texas Red, and that dextran permeation requires TMC1/2 proteins and functional MET channels, supporting the presence of a large permeation pathway and the hypothesis that TMC1 is a pore forming subunit of the MET channel complex.
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