ArticleProceedings of the National Academy of Sciences of the United States of America2020
Structural determinants of protocadherin-15 mechanics and function in hearing and balance perception.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 48 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
- Bayesian-Steered Structure Prediction of Mechanical Biomolecules Using Twisted Diffusion.bioRxiv : the preprint server for biology · 2026Article
- The Impact of Pcdh15 Deficiency on Cellular Energy Metabolism and Oxidative Stress, and Its Role and Mechanism in Hearing Loss.Clinical and experimental otorhinolaryngology · 2026Article
- Genetics of prelingual isolated deafness and Usher syndrome in the Maghreb and Jordan: Harnessing the potential of homozygosity.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Identification of druggable binding sites and small molecules as modulators of TMC1.Communications biology · 2025Article
- 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
- Molecular basis of proteolytic cleavage regulation by the extracellular matrix receptor dystroglycan.Structure (London, England : 1993) · 2024Article
- Nanomechanics of wild-type and mutant dimers of the inner-ear tip-link protein protocadherin 15.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Elasticity and Thermal Stability are Key Determinants of Hearing Rescue by Mini-Protocadherin-15 Proteins.bioRxiv : the preprint server for biology · 2024Article
- Updates on Genetic Hearing Loss: From Diagnosis to Targeted Therapies.Journal of audiology & otology · 2024Article
- PKHD1L1, a gene involved in the stereocilia coat, causes autosomal recessive nonsyndromic hearing loss.Human genetics · 2024Article
- Emergence of slip-ideal-slip behavior in tip-links serve as force filters of sound in hearing.Nature communications · 2024Article
- Article
- Dynamics and functions of E-cadherin complexes in epithelial cell and tissue morphogenesis.Marine life science & technology · 2023Review
- Nanomechanics of wild-type and mutant dimers of the tip-link protein protocadherin 15.bioRxiv : the preprint server for biology · 2023Article
- Mini-PCDH15 gene therapy rescues hearing in a mouse model of Usher syndrome type 1F.Nature communications · 2023Article
- Control of stereocilia length during development of hair bundles.PLoS biology · 2023Article
- Transient interactions drive the lateral clustering of cadherin-23 on membrane.Communications biology · 2023Article
- Common protein-coding variants influence the racing phenotype in galloping racehorse breeds.Communications biology · 2022Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
The vertebrate inner ear, responsible for hearing and balance, is able to sense minute mechanical stimuli originating from an extraordinarily broad range of sound frequencies and intensities or from head movements. Integral to these processes is the tip-link protein complex, which conveys force to open the inner-ear transduction channels that mediate sensory perception. Protocadherin-15 and cadherin-23, two atypically large cadherins with 11 and 27 extracellular cadherin (EC) repeats, are involved in deafness and balance disorders and assemble as parallel homodimers that interact to form the tip link. Here we report the X-ray crystal structure of a protocadherin-15 + cadherin-23 heterotetrameric complex at 2.9-Å resolution, depicting a parallel homodimer of protocadherin-15 EC1-3 molecules forming an antiparallel complex with two cadherin-23 EC1-2 molecules. In addition, we report structures for 10 protocadherin-15 fragments used to build complete high-resolution models of the monomeric protocadherin-15 ectodomain. Molecular dynamics simulations and validated crystal contacts are used to propose models for the complete extracellular protocadherin-15 parallel homodimer and the tip-link bond. Steered molecular dynamics simulations of these models suggest conditions in which a structurally diverse and multimodal protocadherin-15 ectodomain can act as a stiff or soft gating spring. These results reveal the structural determinants of tip-link-mediated inner-ear sensory perception and elucidate protocadherin-15's structural and adhesive properties relevant in disease.
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