美国哈佛医学院Philip J. Kranzusch等研究人员合作揭示细菌gasdermin孔的结构与组装。2024年3月20日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员表示，在病原体感染时，gasdermin（GSDM）会形成膜孔，从而诱导宿主细胞的死亡过程，即所谓的“焦亡”。对人类和小鼠GSDM孔的研究揭示了由24至33个原体组成的集合体的功能和结构，但膜靶向和GSDM孔形成的机制和演化起源仍然未知。

研究人员确定了细菌GSDM（bGSDM）孔的结构，并定义了一种保守的孔组装机制。研究人员对一组bGSDM进行了工程化，以进行特定位点的蛋白水解活化，结果表明，不同的bGSDM形成了不同的孔隙大小，从类似哺乳动物的较小组装到包含50多个原体的超大孔不等。研究人员确定了一种处于活跃的“slinky”状低聚构象中的Vitiosangium bGSDM冷冻电镜结构，并分析了原生脂质环境中的bGSDM孔，从而创建了一个完整的52聚体bGSDM孔的原子级模型。

结合结构分析、分子动力学模拟和细胞检测，这些结果支持GSDM孔组装的分步模型，并表明共价结合的棕榈酰可以在跨膜β链区域形成之前离开疏水鞘并插入膜中。这些结果揭示了自然界中GSDM孔的多样性，并解释了一种古老的翻译后修饰在使宿主细胞程序性死亡中的功能。

附：英文原文

Title: Structure and assembly of a bacterial gasdermin pore

Author: Johnson, Alex G., Mayer, Megan L., Schaefer, Stefan L., McNamara-Bordewick, Nora K., Hummer, Gerhard, Kranzusch, Philip J.

Issue&Volume: 2024-03-20

Abstract: In response to pathogen infection, gasdermin (GSDM) proteins form membrane pores that induce a host cell death process called pyroptosis1,2,3. Studies of human and mouse GSDM pores have revealed the functions and architectures of assemblies comprising 24 to 33 protomers4,5,6,7,8,9, but the mechanism and evolutionary origin of membrane targeting and GSDM pore formation remain unknown. Here we determine a structure of a bacterial GSDM (bGSDM) pore and define a conserved mechanism of pore assembly. Engineering a panel of bGSDMs for site-specific proteolytic activation, we demonstrate that diverse bGSDMs form distinct pore sizes that range from smaller mammalian-like assemblies to exceptionally large pores containing more than 50 protomers. We determine a cryo-electron microscopy structure of a Vitiosangium bGSDM in an active ‘slinky’-like oligomeric conformation and analyse bGSDM pores in a native lipid environment to create an atomic-level model of a full 52-mer bGSDM pore. Combining our structural analysis with molecular dynamics simulations and cellular assays, our results support a stepwise model of GSDM pore assembly and suggest that a covalently bound palmitoyl can leave a hydrophobic sheath and insert into the membrane before formation of the membrane-spanning β-strand regions. These results reveal the diversity of GSDM pores found in nature and explain the function of an ancient post-translational modification in enabling programmed host cell death.

DOI: 10.1038/s41586-024-07216-3

Source: https://www.nature.com/articles/s41586-024-07216-3