Molecular assembly of the aerolysin pore reveals a swirling membrane-insertion mechanism
Molecular assembly of the aerolysin pore reveals a swirling membrane-insertion mechanism
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DOI：
10.1038/nchembio.1312
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发表时间：
2013-10-01
影响因子：
14.8
通讯作者：
Dal Peraro, Matteo
中科院分区：
文献类型：
--
作者：
Degiacomi, Matteo T.;Lacovache, Ioan;Dal Peraro, Matteo
气溶素是β-孔形成毒素超家族的创始成员，其孔结构未知。我们结合了X射线晶体学，cryo-EM，分子动力学和计算建模，以确定气溶素突变体的结构，在其单体和七聚体的形式，被困在孔形成过程的各个阶段。应用基于群体智能的动态建模方法，从而使用从新的X射线结构中提取的气溶素的固有灵活性来充分利用冷冻EM空间约束。使用这种综合策略，我们得到了一个全新的安排prepore构象和气溶素孔，这是完全符合所有的生化数据，迄今为止的近原子结构。在从前孔过渡到孔时，气溶素七聚体显示出独特的协同涡旋运动，伴随着复合物的垂直塌陷，最终导致跨膜β-桶的插入。
Aerolysin is the founding member of a superfamily of (beta-pore-forming toxins whose pore structure is unknown. We have combined X-ray crystallography, cryo-EM, molecular dynamics and computational modeling to determine the structures of aerolysin mutants in their monomeric and heptameric forms, trapped at various stages of the pore formation process. A dynamic modeling approach based on swarm intelligence was applied, whereby the intrinsic flexibility of aerolysin extracted from new X-ray structures was used to fully exploit the cryo-EM spatial restraints. Using this integrated strategy, we obtained a radically new arrangement of the prepore conformation and a near-atomistic structure of the aerolysin pore, which is fully consistent with all of the biochemical data available so far. Upon transition from the prepore to pore, the aerolysin heptamer shows a unique concerted swirling movement, accompanied by a vertical collapse of the complex, ultimately leading to the insertion of a transmembrane beta-barrel.