Molecular Basis of Listeriolysin O pH Dependence

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 an neutral pH. In contrast to other pH-dependent toxins, we have determined that LLO pore-...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 102; no. 35; pp. 12537 - 12542
Main Authors Schuerch, Daniel W., Wilson-Kubalek, Elizabeth M., Tweten, Rodney K., Collier, R. John
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 30.08.2005
National Acad Sciences
Subjects
Aggregation
Bacteria
Bacterial Toxins - chemistry
Bacterial Toxins - genetics
Bacterial Toxins - toxicity
Biological Sciences
Carboxylates
Disulfides
Fluorescence
Genes, Bacterial
Heat-Shock Proteins - chemistry
Heat-Shock Proteins - genetics
Heat-Shock Proteins - toxicity
Heat-Shock Proteins - ultrastructure
Hemolysin Proteins
Hemolysis
Hemolysis - drug effects
Humans
Hydrogen-Ion Concentration
In Vitro Techniques
Listeria monocytogenes
Listeria monocytogenes - chemistry
Listeria monocytogenes - genetics
Listeria monocytogenes - pathogenicity
Microbiology
Microscopy, Electron
Models, Molecular
Molecular biology
Monomers
Multiprotein Complexes
Phagosomes
Point Mutation
Protein Conformation
Protein Denaturation
Protein Structure, Tertiary
Recombinant Proteins - chemistry
Recombinant Proteins - genetics
Recombinant Proteins - toxicity
Recombinant Proteins - ultrastructure
Sensors
Spectrometry, Fluorescence
Temperature
Toxins
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Summary: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 an 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°C. Rapid denaturation is triggered at neutral pH by the premature unfolding of the domain 3 transmembrane β-hairpins; structures that normally form the transmembrane β-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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Author contributions: D.W.S., E.M.W.-K., and R.K.T. designed research; D.W.S., E.M.W.-K., and R.K.T. performed research; E.M.W.-K. contributed new reagents/analytic tools; D.W.S., E.M.W.-K., and R.K.T. analyzed data; and D.W.S. and R.K.T. wrote the paper.
Abbreviations: ANS, 1-anilinonaphthalene-8-sulfonic acid; CDC, cholesterol-dependent cytolysin; LLO, listeriolysin O; LLODS, disulfide-locked LLO; LM, Listeria monocytogenes; PFO, perfringolysin O; TMH, transmembrane β-hairpin.
This paper was submitted directly (Track II) to the PNAS office.
Edited by R. John Collier, Harvard Medical School, Boston, MA, and approved July 5, 2005
To whom correspondence should be addressed at: Department of Microbiology and Immunology, BMSB-1053, 940 Stanton L. Young Boulevard, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104. E-mail: rod-tweten@ouhsc.edu.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0500558102