Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Bacterial Toxins / chemistry*
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Bacterial Toxins / genetics
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Bacterial Toxins / toxicity
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Genes, Bacterial
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Heat-Shock Proteins / chemistry*
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / toxicity
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Heat-Shock Proteins / ultrastructure
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Hemolysin Proteins
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Hemolysis / drug effects
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Humans
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Hydrogen-Ion Concentration
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In Vitro Techniques
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Listeria monocytogenes / chemistry
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Listeria monocytogenes / genetics
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Listeria monocytogenes / pathogenicity
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Microscopy, Electron
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Models, Molecular
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Multiprotein Complexes
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Point Mutation
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Protein Conformation
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Protein Denaturation
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Protein Structure, Tertiary
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / toxicity
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Recombinant Proteins / ultrastructure
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Spectrometry, Fluorescence
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Temperature
Substances
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Bacterial Toxins
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Heat-Shock Proteins
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Hemolysin Proteins
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Multiprotein Complexes
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Recombinant Proteins
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hlyA protein, Listeria monocytogenes