Nanomechanics of wild- type and mutant dimers of the inner- ear tip- link protein protocadherin 15

• 成果类型: Article
• 署名作者: Villasante, Camila M.; Deng, Xinyue; Cohen, Joel E.; Hudspeth, A. J.
• 署名单位: Rockefeller University; Rockefeller University; Columbia University; Columbia University; University of Chicago; Howard Hughes Medical Institute; Rockefeller University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11577
• DOI: 10.1073/pnas.2404829121
• 发表日期: 2024-10-01
• 关键词: usher-syndrome; mechanical transduction; cochlear endolymph; hair-cells

摘要

Mechanical force controls the opening and closing of mechanosensitive ion channels atop the hair bundles of the inner ear. The filamentous tip link connecting transduction channels to the tallest neighboring stereocilium modulates the force transmitted to the channels and thus changes their probability of opening. Each tip link comprises four molecules: a dimer of protocadherin 15 (PCDH15) and a dimer of cadherin 23, all of which are stabilized by Ca2+ binding. Using a high- speed optical trap to examine dimeric PCDH15, we find that the protein's mechanical properties are sensitive to Ca2+ and that can therefore modulate its stiffness without undergoing large unfolding events under physiological conditions. The experimentally determined stiffness of PCDH15 accords with published values for the stiffness of the gating spring, the mechanical element that controls the opening of mechanotransduction channels. When PCDH15 exhibits a occur more frequently under tension and refolding events occur less often than for the the gating spring is critical to the appropriate transmission of force to transduction channels, and hence to hearing.