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

Author

Listed:
  • Eric M. Mulhall

    (Harvard Medical School
    Harvard University)

  • Andrew Ward

    (Harvard Medical School
    Boston Children’s Hospital)

  • Darren Yang

    (Boston Children’s Hospital)

  • Mounir A. Koussa

    (Harvard Medical School
    Harvard University)

  • David P. Corey

    (Harvard Medical School)

  • Wesley P. Wong

    (Boston Children’s Hospital
    Harvard Medical School
    Harvard University)

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.

Suggested Citation

  • Eric M. Mulhall & Andrew Ward & Darren Yang & Mounir A. Koussa & David P. Corey & Wesley P. Wong, 2021. "Single-molecule force spectroscopy reveals the dynamic strength of the hair-cell tip-link connection," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21033-6
    DOI: 10.1038/s41467-021-21033-6
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    Cited by:

    1. Maryna V. Ivanchenko & Daniel M. Hathaway & Alex J. Klein & Bifeng Pan & Olga Strelkova & Pedro De-la-Torre & Xudong Wu & Cole W. Peters & Eric M. Mulhall & Kevin T. Booth & Corey Goldstein & Joseph B, 2023. "Mini-PCDH15 gene therapy rescues hearing in a mouse model of Usher syndrome type 1F," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    2. Nisha Arora & Jagadish P. Hazra & Sandip Roy & Gaurav K. Bhati & Sarika Gupta & K. P. Yogendran & Abhishek Chaudhuri & Amin Sagar & Sabyasachi Rakshit, 2024. "Emergence of slip-ideal-slip behavior in tip-links serve as force filters of sound in hearing," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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