Transmembrane Channel-like (TMC) proteins are a conserved family of membrane proteins involved in various mechanosensory processes. TMC-1 is a component of the pore-forming subunit of the mechanosensory transduction (MET) complex in auditory hair cells, where it works with several auxiliary proteins, including calcium and integrin-binding proteins CIB2/CIB3, transmembrane inner ear (TMIE) protein, lipoma HMGIC fusion partner-like 5 (LHFPL5), the tip-link Protocadherin-15 (PCDH15), as well as PIEZO ion channel proteins. To address the major challenges in experimentally determining the structure and function of the mammalian TMC-1 protein in its apparent conducting state, we performed in silico experiments. We used AlphaFold2 (AF2) to generate models of the mouse TMC-1-CIB2-TMIE complex, which were then subjected to extensive all-atom molecular dynamics (MD) simulations. We identified several potential pore-lining amino acid residues essential for ion permeation (e.g., M412). Indeed, mutations in some of these amino acid residues are linked to hearing loss and deafness, highlighting their functional significance. Our results also show that both amino acid residues and lipids form the wall of the ion permeation pathway. This observation requires detailed analysis for a proposed MET channel with a conductance exceeding 100 pS in hair cells. Additionally, we observed at least two gates along the pathway. A crucial mechanistic detail is that ions undergo partial dehydration as they pass through the putative pore, with TMC-1 ion conduction functions via a non-selective mechanism. These findings are critical for understanding how mammalian TMC-1 supports ion conduction, selectivity, and the role of lipids in its functions, which are essential for advancing targeted development for potential therapies for hearing disorders.
Perez-Flores et al. (Sun,) studied this question.