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

Eric M. Mulhall, Andrew Ward, Darren Yang, Mounir A. Koussa, David P. Corey () and Wesley P. Wong ()
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Eric M. Mulhall: Harvard Medical School
Andrew Ward: Harvard Medical School
Darren Yang: Boston Children’s Hospital
Mounir A. Koussa: Harvard Medical School
David P. Corey: Harvard Medical School
Wesley P. Wong: Boston Children’s Hospital

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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 Ca2+ 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.

Date: 2021
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DOI: 10.1038/s41467-021-21033-6

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