Listeriolysin O (LLO) is a cholesterol-dependent cytolysin that is an essential virulence factor of Listeria monocytogenes. LLO pore-forming activity is pH-dependent; it is active at acidic pH (<6), but not at neutral pH. In contrast to other pH-dependent toxins, we have determined that LLO pore-forming activity is controlled by a rapid and irreversible denaturation of its structure at neutral pH at temperatures >30 degrees C. Rapid denaturation is triggered at neutral pH by the premature unfolding of the domain 3 transmembrane beta-hairpins; structures that normally form the transmembrane beta-barrel. A triad of acidic residues within domain 3 function as the pH sensor and initiate the denaturation of LLO by destabilizing the structure of domain 3. These studies provide a view of a molecular mechanism by which the activity of a bacterial toxin is regulated by pH.
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