Force-dependent structural dynamics of the giant nesprin-2

• 成果类型: Article
• 署名作者: Shang, Fei; Zhang, Yuhang; Ye, Jiaqing; Zhang, Zhuwei; Qi, Xingyu; Chen, Hu; Yu, Miao; Le, Shimin
• 署名单位: Zhejiang University; Zhejiang University; Xiamen University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2517922123
• 发表日期: 2026-01-27
• 页码: e2517922123
• 关键词: nesprins; single-molecule manipulation; mechanobiology; spectrin repeats; FORCE; NUCLEAR-MEMBRANE PROTEIN; LINC COMPLEXES; e-cadherin; LAMIN-A; tension; integrin; reveal; mechanotransduction; CYTOSKELETAL; mechanics

摘要

The nesprin protein family serves as a critical physical bridge between the cytoskeleton-a fundamental structural scaffold and mechanotransduction hub of the cell, and the nucleus-an intriguing and emerging mechanoresponsive element. Due to the external mechanical cues and the nucleo-cytoskeletal dynamics, the nesprins are physiologically under forces. However, the dynamics of nesprins within physiological forces and loading rates remain largely unexplored. In this study, we employ magnetic-tweezers-based single-molecule manipulation alongside molecular dynamic simulations and AlphaFold structural predictions to comprehensively investigate the dynamics of force-bearing spectrin repeat (SR) domains of the giant nesprin-2 protein. Through direct quantification, we unveil that the numerous SRs undergo mechanical unfolding and refolding dynamics with distinct transition rates within several pN scale. Furthermore, we show that the giant nesprin-2 could act as an effective molecular absorber adeptly maintaining forces on the nucleoskeleton and cytoskeleton linkage within a few pN across displacement spans exceeding one mu m. Notably, our findings imply that subtle pN-level mechanical forces intricately modulate nesprin-protein interactions via the dynamics of domain folding and unfolding. Collectively, our study offers a comprehensive understanding of the mechanical characteristics of nesprin-2 giant, shedding light on its pivotal role in nucleoskeleton-cytoskeleton mechanotransduction.