ArticleBiophysical journal2018
A Mechanically Weak Extracellular Membrane-Adjacent Domain Induces Dimerization of Protocadherin-15.
Article in Biophysical journal, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 41 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
- Biallelic variants in CELSR1 cause brain malformations, neurodevelopmental disorders and epilepsy in humans.Nature communications · 2026Article
- Exploring exon excision as a therapeutic intervention strategy for the future treatment ofMolecular therapy. Nucleic acids · 2025Article
- Identification of druggable binding sites and small molecules as modulators of TMC1.Communications biology · 2025Article
- Structural basis for regulation of CELSR1 by a compact module in its extracellular region.Nature communications · 2025Article
- Molecular basis of proteolytic cleavage regulation by the extracellular matrix receptor dystroglycan.Structure (London, England : 1993) · 2024Article
- PKHD1L1 is required for stereocilia bundle maintenance, durable hearing function and resilience to noise exposure.Communications biology · 2024Article
- Elasticity and Thermal Stability are Key Determinants of Hearing Rescue by Mini-Protocadherin-15 Proteins.bioRxiv : the preprint server for biology · 2024Article
- PKHD1L1 is required for stereocilia bundle maintenance, durable hearing function and resilience to noise exposure.bioRxiv : the preprint server for biology · 2024Article
- PKHD1L1, a gene involved in the stereocilia coat, causes autosomal recessive nonsyndromic hearing loss.Human genetics · 2024Article
- Article
- Mini-PCDH15 gene therapy rescues hearing in a mouse model of Usher syndrome type 1F.Nature communications · 2023Article
- Review
- Collective mechanical responses of cadherin-based adhesive junctions as predicted by simulations.Biophysical journal · 2022Article
- Article
- Heterophilic and homophilic cadherin interactions in intestinal intermicrovillar links are species dependent.PLoS biology · 2021Article
- Single-molecule force spectroscopy reveals the dynamic strength of the hair-cell tip-link connection.Nature communications · 2021Article
- Celsr1 adhesive interactions mediate the asymmetric organization of planar polarity complexes.eLife · 2021Article
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
The cadherin superfamily of proteins is defined by the presence of extracellular cadherin (EC) "repeats" that engage in protein-protein interactions to mediate cell-cell adhesion, cell signaling, and mechanotransduction. The extracellular domains of nonclassical cadherins often have a large number of EC repeats along with other subdomains of various folds. Protocadherin-15 (PCDH15), a protein component of the inner-ear tip link filament essential for mechanotransduction, has 11 EC repeats and a membrane adjacent domain (MAD12) of atypical fold. Here we report the crystal structure of a pig PCDH15 fragment including EC10, EC11, and MAD12 in a parallel dimeric arrangement. MAD12 has a unique molecular architecture and folds as a ferredoxin-like domain similar to that found in the nucleoporin protein Nup54. Analytical ultracentrifugation experiments along with size-exclusion chromatography coupled to multiangle laser light scattering and small-angle x-ray scattering corroborate the crystallographic dimer and show that MAD12 induces parallel dimerization of PCDH15 near its membrane insertion point. In addition, steered molecular dynamics simulations suggest that MAD12 is mechanically weak and may unfold before tip-link rupture. Sequence analyses and structural modeling predict the existence of similar domains in cadherin-23, protocadherin-24, and the "giant" FAT and CELSR cadherins, indicating that some of them may also exhibit MAD-induced parallel dimerization.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.