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<p>The cell wall is a complex structure that protects bacteria from environmental threats. Phosphocholine-containing teichoic acids are key cell wall biopolymers critical for host colonization, immune evasion, competence, and persistence in <i>Streptococcus pneumoniae</i>. The flippase TacF, a member of the multidrug/oligosaccharide-lipid/polysaccharide (MOP) superfamily, monitors the phosphocholine content of teichoic acids during transport, yet the underlying mechanism of this process remains unresolved. We present a cryo-EM structure of <i>S. pneumoniae</i> TacF in lipid nanodiscs. In vivo complementation assays and molecular dynamics simulations reveal key residues involved in teichoic acid recognition and transport, while coevolutionary and conservation analyses delineate common mechanistic elements among MOP flippases, indicating a shared mechanism for polyprenyl-diphosphate-linked oligosaccharide lipid transport. Our findings provide mechanistic insights into an essential flippase involved in <i>S. pneumoniae</i> pathogenesis and a potential drug target.</p>

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Mechanistic basis of teichoic acid transport by a gatekeeper flippase

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月25日

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  • Gonzalo Cebrero,
  • Amrutha H. Chidananda,
  • Eric Cester,
  • Julien Dénéréaz,
  • Elif Sena Demir,
  • Alen T. Mathew,
  • D. Ryan Bhowmik,
  • Mario de Capitani,
  • Jean-Louis Reymond,
  • Natarajan Kannan,
  • Fikri Y. Avci,
  • Jan-Willem Veening,
  • Ahmad Reza Mehdipour,
  • Camilo Perez

摘要

The cell wall is a complex structure that protects bacteria from environmental threats. Phosphocholine-containing teichoic acids are key cell wall biopolymers critical for host colonization, immune evasion, competence, and persistence in Streptococcus pneumoniae. The flippase TacF, a member of the multidrug/oligosaccharide-lipid/polysaccharide (MOP) superfamily, monitors the phosphocholine content of teichoic acids during transport, yet the underlying mechanism of this process remains unresolved. We present a cryo-EM structure of S. pneumoniae TacF in lipid nanodiscs. In vivo complementation assays and molecular dynamics simulations reveal key residues involved in teichoic acid recognition and transport, while coevolutionary and conservation analyses delineate common mechanistic elements among MOP flippases, indicating a shared mechanism for polyprenyl-diphosphate-linked oligosaccharide lipid transport. Our findings provide mechanistic insights into an essential flippase involved in S. pneumoniae pathogenesis and a potential drug target.