Structural determinants of protocadherin-15 elasticity and function in inner-ear mechanotransduction
Structural determinants of protocadherin-15 elasticity and function in inner-ear mechanotransduction
Abstract Protocadherin-15 (PCDH15), an atypical member of the cadherin superfamily, is essential for vertebrate hearing and its dysfunction has been associated with deafness and progressive blindness. The PCDH15 ectodomain, made of eleven extracellular cadherin (EC1-11) repeats and a membrane adjacent domain (MAD12), assembles as a parallel homodimer that interacts with cadherin-23 (CDH23) to form the tip link, a fine filament necessary for inner-ear mechanotransduction. Here we report X-ray crystal structures of a PCDH15 + CDH23 heterotetrameric complex and ten PCDH15 fragments that were used to build complete high-resolution models of the monomeric PCDH15 ectodomain. Using molecular dynamics (MD) simulations and validated crystal contacts we propose models for complete PCDH15 parallel homodimers and the tip-link bond. Steered MD simulations of these models predict their strength and suggest conditions in which a multimodal PCDH15 ectodomain can act as a stiff or soft gating spring. These results provide a detailed view of the first molecular steps in inner-ear sensory transduction.
Narui Yoshie、Araya-Secchi Raul、De-la-Torre Pedro、Klanseck Carissa F.、Tamilselvan Elakkiya、Sotomayor Marcos、Wimalasena Lahiru N.、Choudhary Deepanshu、Chen Conghui、Neel Brandon L.
Department of Chemistry and Biochemistry, The Ohio State UniversityDepartment of Chemistry and Biochemistry, The Ohio State University||Structural Biophysics, Section for Neutron and X-ray Science, Niels Bohr Institute, University of CopenhagenDepartment of Chemistry and Biochemistry, The Ohio State UniversityDepartment of Chemistry and Biochemistry, The Ohio State UniversityDepartment of Chemistry and Biochemistry, The Ohio State University||Biophysics Program, The Ohio State UniversityDepartment of Chemistry and Biochemistry, The Ohio State University||The Ohio State Biochemistry Program, The Ohio State University||Biophysics Program, The Ohio State UniversityDepartment of Chemistry and Biochemistry, The Ohio State UniversityDepartment of Chemistry and Biochemistry, The Ohio State UniversityDepartment of Chemistry and Biochemistry, The Ohio State UniversityDepartment of Chemistry and Biochemistry, The Ohio State University||The Ohio State Biochemistry Program, The Ohio State University
耳鼻咽喉科学基础医学分子生物学
Narui Yoshie,Araya-Secchi Raul,De-la-Torre Pedro,Klanseck Carissa F.,Tamilselvan Elakkiya,Sotomayor Marcos,Wimalasena Lahiru N.,Choudhary Deepanshu,Chen Conghui,Neel Brandon L..Structural determinants of protocadherin-15 elasticity and function in inner-ear mechanotransduction[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/695502.点此复制
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