Altered Pore Composition and Flexibility in a Deafness-Associated TMC1 Variant: Insights from Molecular Dynamics...

Area of Science:

• Biophysics
• Molecular Biology
• Genetics

Background:

• Transmembrane channel-like protein 1 (TMC1) is crucial for mechanotransduction in auditory and vestibular hair cells.
• TMC1 forms the ion pore of the mechanotransduction channel, converting mechanical stimuli into electrochemical signals.
• A dimeric structure for TMC1 is proposed, with each monomer potentially forming an independent ion-conducting pore.

Purpose of the Study:

• To investigate the structural and biophysical effects of the p.(M654V) variant in TMC1 using molecular dynamics (MD) simulations.
• To provide atomistic-level insights into how this variant, associated with autosomal recessive deafness, affects the mechanotransduction system.
• To elucidate the molecular mechanisms underlying M654V-associated pathogenicity in TMC1.

Main Methods:

• Molecular dynamics (MD) simulations were employed to compare wild-type TMC1 with the M654V variant.
• Analysis focused on structural properties, pore size, lipid composition, and the electrostatic environment of the channel.
• Investigated local interactions between transmembrane helices and residue 654.

Main Results:

• The M654V variant exhibits altered pore size, lipid composition, and electrostatic environment compared to wild-type TMC1.
• Results suggest independent function of TMC1 monomers and highlight the role of lipids in pore architecture.
• Pathogenicity mechanisms include reduced pore flexibility, a shifted choke point, and decreased lipid incorporation due to disrupted local interactions.

Conclusions:

• The study provides mechanistic insights into TMC1 function and the impact of the M654V variant on hearing.
• Alterations in pore properties and lipid interactions are key factors in M654V-associated deafness.
• Findings underscore the importance of residue 654 and lipid dynamics in TMC1 channel function.