title: Structural basis of pore formation by the bacterial toxin pneumolysin.
abstract: The bacterial toxin pneumolysin is released as a soluble monomer that kills target cells by assembling into large oligomeric rings and forming pores in cholesterol-containing membranes. Using cryo-EM and image processing, we have determined the structures of membrane-surface bound (prepore) and inserted-pore oligomer forms, providing a direct observation of the conformational transition into the pore form of a cholesterol-dependent cytolysin. In the pore structure, the domains of the monomer separate and double over into an arch, forming a wall sealing the bilayer around the pore. This transformation is accomplished by substantial refolding of two of the four protein domains along with deformation of the membrane. Extension of protein density into the bilayer supports earlier predictions that the protein inserts beta hairpins into the membrane. With an oligomer size of up to 44 subunits in the pore, this assembly creates a transmembrane channel 260 A in diameter lined by 176 beta strands.
authors.affiliation: School of Crystallography and Institute of Structural Molecular Biology, Birkbeck College, Malet Street, London WC1E 7HX, United Kingdom.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Tilley
authors.forename: Elena V
authors.initials: EV
authors.lastname: Orlova
authors.forename: Robert J C
authors.initials: RJ
authors.lastname: Gilbert
authors.forename: Peter W
authors.initials: PW
authors.lastname: Andrew
authors.forename: Helen R
authors.initials: HR
authors.lastname: Saibil
mesh_terms: D001425:Bacterial Outer Membrane Proteins / Q000737:chemistry / Q000648:ultrastructure; D001426:Bacterial Proteins / Q000737:chemistry* / Q000648:ultrastructure*; D002462:Cell Membrane / Q000737:chemistry / Q000648:ultrastructure; D002784:Cholesterol / Q000737:chemistry; D020285:Cryoelectron Microscopy; D008081:Liposomes / Q000737:chemistry; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D013296:Streptococcus pneumoniae / Q000737:chemistry*; D013301:Streptolysins / Q000737:chemistry*
chemical_list: D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D008081:Liposomes; D013301:Streptolysins; C032290:plY protein, Streptococcus pneumoniae; D002784:Cholesterol