Single-molecule force spectroscopy reveals intra- and intermolecular interactions of Caenorhabditis elegans HMP-1 during mechanotransduction

• 成果类型: Article
• 署名作者: Le, Shimin; Yu, Miao; Fu, Chaoyu; Heier, Jonathon A.; Martin, Sterling; Hardin, Jeff; Yan, Jie
• 署名单位: National University of Singapore; Xiamen University; Zhejiang University; Zhejiang University; National University of Singapore; University of Wisconsin System; University of Wisconsin Madison; University of Wisconsin System; University of Wisconsin Madison; National University of Singapore; TJU-NUS Joint Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13221
• DOI: 10.1073/pnas.2400654121
• 发表日期: 2024-09-10
• 关键词: cell-cell adhesion; alpha-catenin; beta-catenin; mechanical stability; binding; protein; activation; tension; bond

摘要

The Caenorhabditis elegans HMP-2/HMP-1 complex, akin to the mammalian /3-catenin- a-catenin complex, serves as a critical mechanosensor at cell-cell adherens junctions, transducing tension between HMR-1 (also known as cadherin in mammals) and the actin cytoskeleton. Essential for embryonic development and tissue integrity in C. elegans, this complex experiences tension from both internal actomyosin contractility and external mechanical microenvironmental perturbations. While offering a valuable evolutionary comparison to its mammalian counterpart, the impact of tension on the mechanical stability of HMP-1 and HMP-2/HMP-1 interactions remains unexplored. In this study, we directly quantified the mechanical stability of full-length HMP-1 and its force-bearing modulation domains (M1-M3), as well as the HMP-2/HMP-1 interface. Notably, the M1 domain in HMP-1 exhibits significantly higher mechanical stability than its mammalian analog, attributable to interdomain interactions with M2-M3. Introducing salt bridge mutations in the M3 domain weakens the mechanical stability of the M1 domain. Moreover, the intermolecular HMP-2/HMP-1 interface surpasses its mammalian counterpart in mechanical stability, enabling it to support the mechanical activation of the autoinhibited M1 domain for mechanotransduction. Additionally, the phosphomimetic mutation Y69E in HMP-2 weakens the mechanical stability of the HMP-2/HMP-1 interface, compromising the force-transmission molecular linkage and its associated mechanosensing functions. Collectively, these findings provide mechanobiological insights into the C. elegans HMP-2/HMP-1 complex, highlighting the impact of salt bridges on mechanical stability in a-catenin and demonstrating the evolutionary conservation of the mechanical switch mechanism activating the HMP-1 modulation domain for protein binding at the single-molecule level.