Structures of perfringolysin O suggest a pathway for activation of cholesterol-dependent cytolysins.
Cholesterol-dependent cytolysins (CDCs), a large family of bacterial toxins, are secreted as water-soluble monomers and yet are capable of generating oligomeric pores in membranes. Previous work has demonstrated that large scale structural rearrangements occur during this transition but the detailed mechanism by which these changes take place remains a puzzle. Despite evidence of structural and functional couplings between domains 3 and 4, the crystal structure of the CDC, perfringolysin O (PFO), shows the two domains do not make direct contact. Here, we present crystal structures of PFO that demonstrate movements of domain 4 are sufficient to trigger conformational changes that are transmitted through the molecule to the distant domain 3. These coupled movements result in a loss of many contacts between domain 3 and rest of the molecule that would eventually lead to the exposure of transmembrane regions in preparation for membrane insertion. The structures reveal a detailed molecular pathway that may be the basis for the allosteric transition that occurs on initial membrane binding leading to the exposure of membrane-spanning regions in a domain distant from the initial site of interaction.
Rossjohn
Jamie
J
Biota Structural Biology Laboratory, St. Vincent's Institute of Medical Research, 9 Princes St, Fitzroy, Victoria 3065, Australia.
Polekhina
Galina
G
Feil
Susanne C
SC
Morton
Craig J
CJ
Tweten
Rodney K
RK
Parker
Michael W
MW
D001427:Bacterial Toxins / Q000737:chemistry* / Q000378:metabolism; D002784:Cholesterol / Q000502:physiology*; D018360:Crystallography, X-Ray; D019281:Dimerization; D006460:Hemolysin Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D006863:Hydrogen-Ion Concentration; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008958:Models, Molecular; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012399:Rotation; D014364:Tryptophan / Q000502:physiology
D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; C020452:Clostridium perfringens theta-toxin; D014364:Tryptophan; D002784:Cholesterol