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

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  • Yukai Wang

    (Xiamen University
    Zhejiang University School of Medicine)

  • Jiaqing Ye

    (Xiamen University)

  • Xian Liu

    (Zhejiang University School of Medicine)

  • Zhuwei Zhang

    (Xiamen University)

  • Fei Shang

    (Xiamen University
    Xiamen University)

  • Xingyu Qi

    (Xiamen University)

  • Yuhang Zhang

    (Xiamen University)

  • Jingyi Du

    (Zhejiang University School of Medicine)

  • Hao Sun

    (Xiamen University
    University of Chinese Academy of Sciences)

  • Jiashu Xu

    (Xiamen University)

  • Hu Chen

    (Xiamen University
    University of Chinese Academy of Sciences)

  • Miao Yu

    (Zhejiang University School of Medicine)

  • Shimin Le

    (Xiamen University)

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.

Suggested Citation

  • Yukai Wang & Jiaqing Ye & Xian Liu & Zhuwei Zhang & Fei Shang & Xingyu Qi & Yuhang Zhang & Jingyi Du & Hao Sun & Jiashu Xu & Hu Chen & Miao Yu & Shimin Le, 2025. "Mechanically weak and highly dynamic state of mechanosensitive titin Ig domains induced by proline isomerization," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57989-y
    DOI: 10.1038/s41467-025-57989-y
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