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<p>The Tol-Pal system is essential for maintaining outer membrane (OM) stability during cell division in Gram-negative bacteria. The inner membrane complex TolQRA harnesses proton motive force (PMF) to establish transient interactions within the periplasm, thereby coordinating cell envelope remodeling and facilitating OM invagination at division sites. However, the precise mechanism remains unclear. Here, we present cryo-electron microscopy structures of <i>Escherichia coli</i> TolQRA in multiple conformational states at 2.92–3.52 Å resolution, revealing rotary dynamics within the complex. Computational simulations reveal a proton-conductive channel comprising the putative proton-accepting residue Asp23 and the conserved polar residues Thr145 and Thr178, with monitored inter-residue distances providing support for a proton-driven rotary mechanism. Site-directed mutagenesis combined with functional assays validates the AlphaFold-predicted structure of the periplasmic domains of TolR and TolA, and further pinpoints critical residues required for complex function. Together, these findings advance our understanding of TolQRA-mediated proton transduction and offer new avenues for antibiotic drug development.</p>

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Deciphering the molecular mechanism of the bacterial division motor TolQRA

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月4日

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  • Chongrong Shen,
  • Teng Xie,
  • Yongbo Luo,
  • Fangyuan Zhao,
  • Xin Wang,
  • Zhibo Zhang,
  • Jie Pang,
  • Jierou Zhang,
  • Xintan Dong,
  • Shenghai Chang,
  • Bi-Sen Ding,
  • Binwu Ying,
  • Wei Chi,
  • Zhaoming Su,
  • Ruhong Zhou,
  • Xiaodi Tang,
  • Haohao Dong

摘要

The Tol-Pal system is essential for maintaining outer membrane (OM) stability during cell division in Gram-negative bacteria. The inner membrane complex TolQRA harnesses proton motive force (PMF) to establish transient interactions within the periplasm, thereby coordinating cell envelope remodeling and facilitating OM invagination at division sites. However, the precise mechanism remains unclear. Here, we present cryo-electron microscopy structures of Escherichia coli TolQRA in multiple conformational states at 2.92–3.52 Å resolution, revealing rotary dynamics within the complex. Computational simulations reveal a proton-conductive channel comprising the putative proton-accepting residue Asp23 and the conserved polar residues Thr145 and Thr178, with monitored inter-residue distances providing support for a proton-driven rotary mechanism. Site-directed mutagenesis combined with functional assays validates the AlphaFold-predicted structure of the periplasmic domains of TolR and TolA, and further pinpoints critical residues required for complex function. Together, these findings advance our understanding of TolQRA-mediated proton transduction and offer new avenues for antibiotic drug development.