Single-molecule force spectroscopy reveals the dynamic strength of the hair-cell tip-link connection

• Published in: Nature communications 2021-02, Vol.12 (1), p.849-849, Article 849
• Main Authors: Mulhall, Eric M., Ward, Andrew, Yang, Darren, Koussa, Mounir A., Corey, David P., Wong, Wesley P.
• Format: Article
• Language: English
• Subjects: 631/378/2619/1533; 631/57/2265; 631/57/2272/2273; 82/80; 96/10; 96/63; Adhesive bonding; Animals; Biomechanical Phenomena; Calcium; Calcium - metabolism; Calcium ions; Conversion; Deafness; Deafness - genetics; Dimerization; Domains; Elasticity; Extracellular Space - metabolism; Hair; Hair Cells, Auditory - physiology; Humanities and Social Sciences; Mechanical properties; Mechanical stimuli; Mechanotransduction; Mice; multidisciplinary; Mutation; Mutation - genetics; Neurosciences; Phenotype; Phenotypes; Proteins; Proteins - metabolism; Science; Science (multidisciplinary); Single Molecule Imaging; Spectroscopy; Stimuli; Vestibular stimuli; Vestibular system
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21033-6

The conversion of auditory and vestibular stimuli into electrical signals is initiated by force transmitted to a mechanotransduction channel through the tip link, a double stranded protein filament held together by two adhesion bonds in the middle. Although thought to form a relatively static structure, the dynamics of the tip-link connection has not been measured. Here, we biophysically characterize the strength of the tip-link connection at single-molecule resolution. We show that a single tip-link bond is more mechanically stable relative to classic cadherins, and our data indicate that the double stranded tip-link connection is stabilized by single strand rebinding facilitated by strong cis-dimerization domains. The measured lifetime of seconds suggests the tip-link is far more dynamic than previously thought. We also show how Ca 2+ alters tip-link lifetime through elastic modulation and reveal the mechanical phenotype of a hereditary deafness mutation. Together, these data show how the tip link is likely to function during mechanical stimuli. The conversion of auditory and vestibular stimuli into electrical signals is initiated by force transmitted to a mechanotransduction channel through the tip link. Here authors show that a single tip-link bond is more mechanically stable relative to classic cadherins, and that the double stranded tip-link connection is stabilized by single strand rebinding facilitated by strong cis-dimerization domains.