title: Molecular assembly of the aerolysin pore reveals a swirling membrane-insertion mechanism.
abstract: Aerolysin is the founding member of a superfamily of β-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 β-barrel.
authors.affiliation: 1] Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. [2] [3].
authors.forename: Matteo T
authors.initials: MT
authors.lastname: Degiacomi
authors.forename: Ioan
authors.initials: I
authors.lastname: Iacovache
authors.forename: Lucile
authors.initials: L
authors.lastname: Pernot
authors.forename: Mohamed
authors.initials: M
authors.lastname: Chami
authors.forename: Misha
authors.initials: M
authors.lastname: Kudryashev
authors.forename: Henning
authors.initials: H
authors.lastname: Stahlberg
authors.forename: F Gisou
authors.initials: FG
authors.lastname: van der Goot
authors.forename: Matteo
authors.initials: M
authors.lastname: Dal Peraro
mesh_terms: D048409:Aeromonas salmonicida / Q000737:chemistry*; D001427:Bacterial Toxins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D017354:Point Mutation; D052899:Pore Forming Cytotoxic Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation
chemical_list: D001427:Bacterial Toxins; D008565:Membrane Proteins; D052899:Pore Forming Cytotoxic Proteins; C032676:aerolysin
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