Membrane-dependent conformational changes initiate cholesterol-dependent cytolysin oligomerization and intersubunit beta-strand alignment

Nature Structural & Molecular Biology
Rajesh RamachandranArthur E Johnson

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 beta-strand that forms the monomer-monomer interface and is required for oligomer assembly. The beta-strands that form the interface each contain a single aromatic residue, and these aromatics appear to stack, thereby aligning the transmembrane beta-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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Citations

Oct 13, 2012·Chemical Reviews·Ekaterina M Nestorovich, Sergey M Bezrukov
Apr 9, 2013·Nature Chemical Biology·Takehiro K SatoArthur E Johnson
May 5, 2005·Nature Structural & Molecular Biology·Hagan BayleyMark Wallace
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