Cholesterol promotes Cytolysin A activity by stabilizing the intermediates during pore formation

Abstract

Pore-forming toxins (PFTs) are the largest class of bacterial exotoxins mediating virulence. Soluble toxin monomers oligomerize upon binding to cellular membrane and convert to stable membrane-integrated pores, causing cell death. This conversion to an active form occurs in absence of extrinsic factors and is governed solely by molecular determinants in the protein and target membrane. Here we demonstrate the existence of cholesterol-binding motifs in ClyA, which stabilize structural intermediates in the assembly pathway in presence of cholesterol. Our finding elucidates the basis for selective targeting of the toxin to eukaryotic membranes. Molecular engineering of these signatures could advance application of PFTs in cytolytic therapy.