Multi-domain interaction mediated strength-building in human α-actinin dimers unveiled by direct single-molecule quantification

Yuhang Zhang, Jingyi Du, Xian Liu, Fei Shang, Yunxin Deng, Jiaqing Ye, Yukai Wang, Jie Yan, Hu Chen (), Miao Yu () and Shimin Le ()
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Yuhang Zhang: Xiamen University
Jingyi Du: Zhejiang University School of Medicine
Xian Liu: Zhejiang University School of Medicine
Fei Shang: Xiamen University
Yunxin Deng: National University of Singapore
Jiaqing Ye: Xiamen University
Yukai Wang: Xiamen University
Jie Yan: National University of Singapore
Hu Chen: Xiamen University
Miao Yu: Zhejiang University School of Medicine
Shimin Le: Xiamen University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract α-Actinins play crucial roles in cytoskeletal mechanobiology by acting as force-bearing structural modules that orchestrate and sustain the cytoskeletal framework, serving as pivotal hubs for diverse mechanosensing proteins. The mechanical stability of α-actinin dimer, a determinant of its functional state, remains largely unexplored. Here, we directly quantify the force-dependent lifetimes of homo- and hetero-dimers of human α-actinins, revealing an ultra-high mechanical stability of the dimers associated with > 100 seconds lifetime within 40 pN forces under shear-stretching geometry. Intriguingly, we uncover that the strong dimer stability is arisen from much weaker sub-domain pair interactions, suggesting the existence of distinct dimerized functional states of the dimer, spanning a spectrum of mechanical stability, with the spectrin repeats (SRs) in folded or unfolded conformation. In essence, our study supports a potent mechanism for building strength in biomolecular dimers through weak, multiple sub-domain interactions, and illuminates multifaceted roles of α-actinin dimers in cytoskeletal mechanics and mechanotransduction.

Date: 2024
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DOI: 10.1038/s41467-024-50430-w

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