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<p>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 &#xa0;~ 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月20日

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  • 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

摘要

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.