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Cryo-EM reveals a right-handed double-helix dimer architecture of PCDH15

Xiaoping Liang1, Roshan Pathak2, Xufeng Qiu1

  • 1The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.

Proceedings of the National Academy of Sciences of the United States of America
|June 9, 2026
PubMed

Insights

Protocadherin 15 (PCDH15) forms a right-handed double helix in the inner ear's tip links. This structure is crucial for mechanical sensing by hair cells and force transmission to mechanotransduction channels.

Area of Science:

  • Molecular biology
  • Structural biology
  • Auditory neuroscience

Background:

  • Tip links connect stereocilia in inner ear hair cells, transmitting force to mechanotransduction (MET) channels.
  • Tip links are composed of protocadherin 15 (PCDH15) and cadherin 23, forming a ~150 nm filament.
  • Previous electron microscopy suggested tip links might be right-handed double helices, but direct structural evidence was absent.

Purpose of the Study:

  • To determine the structure of the extracellular PCDH15 domain.
  • To provide direct structural evidence for the in vivo conformation of tip links.
  • To elucidate the molecular basis of PCDH15's role in mechanical sensing.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) to determine the structure of the extracellular PCDH15 domain.
  • Analysis of dimerization interfaces within the PCDH15 structure.
  • Functional studies assessing the impact of PCDH15 mutations on MET.

Main Results:

  • Two PCDH15 molecules form a parallel cis dimer, creating a right-handed double helix.
  • Dimerization is stabilized by strand crossovers and parallel contacts.
  • Mutations in PCDH15 dimerization domains were found to impair mechanotransduction (MET).

Conclusions:

  • PCDH15 forms a right-handed double helix, establishing the molecular foundation for tip link structure.
  • This helical structure is essential for the mechanical sensing function of hair cells.
  • The findings clarify how PCDH15 contributes to force transmission in the auditory system.
Keywords:
PCDH15cryo-EMhair cellmechanotransductiontip link

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