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 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.
Schuerch
Daniel W
DW
Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Wilson-Kubalek
Elizabeth M
EM
Tweten
Rodney K
RK
D001427:Bacterial Toxins / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity; D005798:Genes, Bacterial; D006360:Heat-Shock Proteins / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity / Q000648:ultrastructure; D006460:Hemolysin Proteins; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008089:Listeria monocytogenes / Q000737:chemistry / Q000235:genetics / Q000472:pathogenicity; D008854:Microscopy, Electron; D008958:Models, Molecular; D046912:Multiprotein Complexes; D017354:Point Mutation; D011487:Protein Conformation; D011489:Protein Denaturation; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000633:toxicity / Q000648:ultrastructure; D013050:Spectrometry, Fluorescence; D013696:Temperature
D001427:Bacterial Toxins; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D046912:Multiprotein Complexes; D011994:Recombinant Proteins; C038705:hlyA protein, Listeria monocytogenes