Molecular assembly of the aerolysin pore reveals a swirling membrane-insertion mechanism

Nat Chem Biol. 2013 Oct;9(10):623-9. doi: 10.1038/nchembio.1312. Epub 2013 Aug 4.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aeromonas salmonicida / chemistry*
  • Bacterial Toxins / chemistry*
  • Bacterial Toxins / genetics
  • Bacterial Toxins / metabolism*
  • Crystallography, X-Ray
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Point Mutation
  • Pore Forming Cytotoxic Proteins / chemistry*
  • Pore Forming Cytotoxic Proteins / genetics
  • Pore Forming Cytotoxic Proteins / metabolism*
  • Protein Conformation

Substances

  • Bacterial Toxins
  • Membrane Proteins
  • Pore Forming Cytotoxic Proteins
  • aerolysin