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An elastic element in the protocadherin-15 tip link of the inner ear

Author

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  • Raul Araya-Secchi

    (The Ohio State University)

  • Brandon L. Neel

    (The Ohio State University)

  • Marcos Sotomayor

    (The Ohio State University)

Abstract

Tip link filaments convey force and gate inner-ear hair-cell transduction channels to mediate perception of sound and head movements. Cadherin-23 and protocadherin-15 form tip links through a calcium-dependent interaction of their extracellular domains made of multiple extracellular cadherin (EC) repeats. These repeats are structurally similar, but not identical in sequence, often featuring linkers with conserved calcium-binding sites that confer mechanical strength to them. Here we present the X-ray crystal structures of human protocadherin-15 EC8–EC10 and mouse EC9–EC10, which show an EC8–9 canonical-like calcium-binding linker, and an EC9–10 calcium-free linker that alters the linear arrangement of EC repeats. Molecular dynamics simulations and small-angle X-ray scattering experiments support this non-linear conformation. Simulations also suggest that unbending of EC9–10 confers some elasticity to otherwise rigid tip links. The new structure provides a first view of protocadherin-15’s non-canonical EC linkers and suggests how they may function in inner-ear mechanotransduction, with implications for other cadherins.

Suggested Citation

  • Raul Araya-Secchi & Brandon L. Neel & Marcos Sotomayor, 2016. "An elastic element in the protocadherin-15 tip link of the inner ear," Nature Communications, Nature, vol. 7(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13458
    DOI: 10.1038/ncomms13458
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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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