Abstract
Cholesterol-dependent cytolysins are bacterial protein toxins that bind to cholesterol-containing membranes, form oligomeric complexes and insert into the bilayer to create large aqueous pores. Membrane-dependent structural rearrangements required to initiate the oligomerization of perfringolysin O monomers have been identified, as have the monomer-monomer interaction surfaces, using site-specific mutagenesis, disulfide trapping and multiple fluorescence techniques. Upon binding to the membrane, a structural element in perfringolysin O moves to expose the edge of a previously hidden β-strand that forms the monomer-monomer interface and is required for oligomer assembly. The β-strands that form the interface each contain a single aromatic residue, and these aromatics appear to stack, thereby aligning the transmembrane β-hairpins of adjacent monomers in the proper register for insertion. Collectively, these data reveal a novel membrane binding–dependent mechanism for regulating cytolysin monomer-monomer association and pore formation.
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This work was supported by US National Institutes of Health grant AI 37657 and the Robert A. Welch Foundation.
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Ramachandran, R., Tweten, R. & Johnson, A. Membrane-dependent conformational changes initiate cholesterol-dependent cytolysin oligomerization and intersubunit β-strand alignment. Nat Struct Mol Biol 11, 697–705 (2004). https://doi.org/10.1038/nsmb793
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DOI: https://doi.org/10.1038/nsmb793
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