Mechanically weak and highly dynamic state of mechanosensitive titin Ig domains induced by proline isomerization

Yukai Wang, Jiaqing Ye, Xian Liu, Zhuwei Zhang, Fei Shang, Xingyu Qi, Yuhang Zhang, Jingyi Du, Hao Sun, Jiashu Xu, Hu Chen (), Miao Yu () and Shimin Le ()
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Yukai Wang: Xiamen University
Jiaqing Ye: Xiamen University
Xian Liu: Zhejiang University School of Medicine
Zhuwei Zhang: Xiamen University
Fei Shang: Xiamen University
Xingyu Qi: Xiamen University
Yuhang Zhang: Xiamen University
Jingyi Du: Zhejiang University School of Medicine
Hao Sun: Xiamen University
Jiashu Xu: Xiamen University
Hu Chen: Xiamen University
Miao Yu: Zhejiang University School of Medicine
Shimin Le: Xiamen University

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Titin, essential for mechano-homeostasis in cardiac and skeletal sarcomere, contains numerous mechanosensitive immunoglobulin-like (Ig) domains in its I-band region. However, how proline isomerization and cysteine-mediated disulfide bond collectively regulate Ig domain dynamics within the physiological force range remains unclear. Here, we use single-molecule force spectroscopy to quantify the proximal Ig1 domain, revealing that proline isomerization leads to two native states–trans and cis states–with distinct mechanical and thermal stabilities. The trans-Ig1 unfolds at forces of ~ 5 pN, which is over 50 pN lower than that of cis-Ig1, and unfolds 1000 times faster under physiological forces. Furthermore, such proline induced dual-state is likely shared feature across majority of I-band Ig domains. Additionally, reduced cis- and trans-Ig1 exhibit catch-slip bond unfolding, while oxidized forms display slip-catch-slip unfolding. This study offers insight into effective modulation of proline isomerization and disulfide bond in regulating mechanosensitive proteins within the physiological force range.

Date: 2025
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DOI: 10.1038/s41467-025-57989-y

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