Biological complexity: hearing mechanism (Introduction)

by David Turell , Sunday, October 16, 2022, 16:12 (769 days ago) @ David Turell

How a specialized protein works:

https://www.sciencealert.com/finally-scientists-have-figured-out-a-key-molecular-mechan...

"Researchers have known for some time that the transmembrane channel-like protein 1 (TMC1) complex performs an important role in hearing, but the exact makeup has remained elusive.

"This is the last sensory system in which that fundamental molecular machinery has remained unknown," says senior author Eric Gouaux, a senior biochemist at OHSU.

"Thanks to this new research, published in Nature, we now know that this protein complex operates as a tension-sensitive ion channel that opens and closes depending upon the movement of hairs inside the inner ear.

"Using electron microscopy, the researchers discovered that the protein complex "resembles an accordion", with subunits "poised like handles" on either side.

"Sound waves traveling through the ear strike the eardrum (tympanic membrane), then to the inner ear where it jiggles the ossicles; three of the body's tiniest bones. The ossicles strike the snail-like cochlear, which in turn brushes microscopic finger-like hairs called stereocilia against membranes.

"These stereocilia are embedded in cells that have the ion channels formed by the TMC1 complex that open and close as the hairs move, sending electrical signals along the auditory nerve to the brain to be interpreted as sound."

Original paper abstract:

https://www.nature.com/articles/s41586-022-05314-8

"The initial step in the sensory transduction pathway underpinning hearing and balance in mammals involves the conversion of force into the gating of a mechanosensory transduction channel1. Despite the profound socioeconomic impacts of hearing disorders and the fundamental biological significance of understanding mechanosensory transduction, the composition, structure and mechanism of the mechanosensory transduction complex have remained poorly characterized. Here we report the single-particle cryo-electron microscopy structure of the native transmembrane channel-like protein 1 (TMC-1) mechanosensory transduction complex isolated from Caenorhabditis elegans. The two-fold symmetric complex is composed of two copies each of the pore-forming TMC-1 subunit, the calcium-binding protein CALM-1 and the transmembrane inner ear protein TMIE. CALM-1 makes extensive contacts with the cytoplasmic face of the TMC-1 subunits, whereas the single-pass TMIE subunits reside on the periphery of the complex, poised like the handles of an accordion. A subset of complexes additionally includes a single arrestin-like protein, arrestin domain protein (ARRD-6), bound to a CALM-1 subunit. Single-particle reconstructions and molecular dynamics simulations show how the mechanosensory transduction complex deforms the membrane bilayer and suggest crucial roles for lipid–protein interactions in the mechanism by which mechanical force is transduced to ion channel gating.*

Comment: so many parts working in a coordinated fashion must be considered irreducibly complex and must be created all at once by design.