ArticleBiochemistry2018
Tuning Inner-Ear Tip-Link Affinity Through Alternatively Spliced Variants of Protocadherin-15.
Article in Biochemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 22 citations in OpenAlex.
- Molecular identity of the mechanotransduction machinery in inner ear hair cells and mechanotransduction-linked hearing loss.Fundamental research · 2026Review
- Cryo-EM reveals a right-handed double-helix dimer architecture of PCDH15.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Cdh23 Gene Mutation-Induced Vestibular Dysfunction in Mice: Abnormal Stereocilia Bundle and Otolith Development and Activation of p53/FoxO Signaling Pathway.Journal of molecular neuroscience : MN · 2025Article
- Transient interactions drive the lateral clustering of cadherin-23 on membrane.Communications biology · 2023Article
- Review
- In situ structure of intestinal apical surface reveals nanobristles on microvilli.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Heterophilic and homophilic cadherin interactions in intestinal intermicrovillar links are species dependent.PLoS biology · 2021Article
- Usher syndrome type 1-associated gene, pcdh15b, is required for photoreceptor structural integrity in zebrafish.Disease models & mechanisms · 2021Article
- DNA Methylation Signature in Mononuclear Cells and Proinflammatory Cytokines May Define Molecular Subtypes in Sporadic Meniere Disease.Biomedicines · 2021Article
- Single-molecule force spectroscopy reveals the dynamic strength of the hair-cell tip-link connection.Nature communications · 2021Article
- Inhibition of a transcriptional repressor rescues hearing in a splicing factor-deficient mouse.Life science alliance · 2020Article
- Desmosome architecture derived from molecular dynamics simulations and cryo-electron tomography.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Structural determinants of protocadherin-15 mechanics and function in hearing and balance perception.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- A Mechanically Weak Extracellular Membrane-Adjacent Domain Induces Dimerization of Protocadherin-15.Biophysical journal · 2018Article
- Sensory Hair Cells: An Introduction to Structure and Physiology.Integrative and comparative biology · 2018Review
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Human hearing relies upon the tip-to-tip interaction of two nonclassical cadherins, protocadherin-15 (PCDH15) and cadherin-23 (CDH23). Together, these proteins form a filament called the tip link that connects neighboring stereocilia of mechanosensitive hair cells. As sound waves enter the cochlea, the stereocilia deflect and tension is applied to the tip link, opening nearby transduction channels. Disruption of the tip link by loud sound or calcium chelators eliminates transduction currents and illustrates that tip-link integrity is critical for mechanosensing. Tip-link remodeling after disruption is a dynamic process, which can lead to the formation of atypical complexes that incorporate alternatively spliced variants of PCDH15. These variants are categorized into six groups (N1-N6) based upon differences in the first two extracellular cadherin (EC) repeats. Here, we characterized the two N-terminal EC repeats of all PCDH15 variants (pcdh15(N1) to pcdh15(N6)) and combined these variants to test complex formation. We solved the crystal structure of a new complex composed of CDH23 EC1-2 (cdh23) and pcdh15(N2) at 2.3 Å resolution and compared it to the canonical cdh23-pcdh15(N1) complex. While there were subtle structural differences, the binding affinity between cdh23 and pcdh15(N2) is ∼6 times weaker than cdh23 and pcdh15(N1) as determined by surface plasmon resonance analysis. Steered molecular dynamics simulations predict that the unbinding force of the cdh23-pcdh15(N2) complex can be lower than the canonical tip link. Our results demonstrate that alternative heterophilic tip-link structures form stable protein-protein interactions in vitro and suggest that homophilic PCDH15-PCDH15 tip links form through the interaction of additional EC repeats.
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