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<p>Malaria-causing <i>Plasmodium</i> parasites must pass through several host cell types to complete their life cycle. This cell traversal is facilitated by perforin-like proteins (PLPs), among which PLP2 is essential for erythrocyte rupture by gametocytes. However, the mechanism by which PLP2 forms pores is not yet understood. Here, we combine cryo-electron microscopy and tomography to reveal the structural basis of <i>Plasmodium vivax</i> PLP2-mediated membrane attack. PvPLP2 assembles on lipid bilayers into heterogeneous arc- and ring-shaped pores with variable stoichiometries. Among them, we determine the structure of a 17-subunit pore complex in which the pore-forming MACPF domains form the central β-barrel, while the peripheral Apicomplexan PLP C-terminal β-pleated sheet (APCβ) domains anchor the complex to the membrane surface. A disulfide-stabilized mutant captures an intermediate pre-pore complex prior to membrane insertion, delineating the structural transitions that underpin β-barrel deployment. Functionally, PvPLP2 acts preferentially on the inner leaflet of the erythrocyte membrane, a specificity driven by its affinity for negatively charged lipids. Together, these findings establish the pore-formation pathway for a key <i>Plasmodium</i> virulence factor and provide a structural framework for rational design of transmission-blocking agents that prevent gametocyte egress.</p>

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Molecular mechanism of pore formation by Plasmodium Perforin-like Protein 2

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月31日

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  • Yu Zhang,
  • Lijie Zhong,
  • Yun Song,
  • Mingcheng Guo,
  • Keli Ren,
  • Tingting Yang,
  • Yixin Huang,
  • Ilia Sirotkin,
  • Gangshun Yi,
  • Fang Jiao,
  • Peijun Zhang,
  • Robert J. C. Gilbert,
  • Tao Ni,
  • Xiulian Yu

摘要

Malaria-causing Plasmodium parasites must pass through several host cell types to complete their life cycle. This cell traversal is facilitated by perforin-like proteins (PLPs), among which PLP2 is essential for erythrocyte rupture by gametocytes. However, the mechanism by which PLP2 forms pores is not yet understood. Here, we combine cryo-electron microscopy and tomography to reveal the structural basis of Plasmodium vivax PLP2-mediated membrane attack. PvPLP2 assembles on lipid bilayers into heterogeneous arc- and ring-shaped pores with variable stoichiometries. Among them, we determine the structure of a 17-subunit pore complex in which the pore-forming MACPF domains form the central β-barrel, while the peripheral Apicomplexan PLP C-terminal β-pleated sheet (APCβ) domains anchor the complex to the membrane surface. A disulfide-stabilized mutant captures an intermediate pre-pore complex prior to membrane insertion, delineating the structural transitions that underpin β-barrel deployment. Functionally, PvPLP2 acts preferentially on the inner leaflet of the erythrocyte membrane, a specificity driven by its affinity for negatively charged lipids. Together, these findings establish the pore-formation pathway for a key Plasmodium virulence factor and provide a structural framework for rational design of transmission-blocking agents that prevent gametocyte egress.