Ion channels and bacterial infection: the case of beta-barrel pore-forming protein toxins of Staphylococcus aureus.
Staphylococcus aureus strains causing human pathologies produce several toxins, including a pore-forming protein family formed by the single-component alpha-hemolysin and the bicomponent leukocidins and gamma-hemolysins. The last comprise two protein elements, S and F, that co-operatively form the active toxin. alpha-Hemolysin is always expressed by S. aureus strains, whereas bicomponent leukotoxins are more specifically involved in a few diseases. X-ray crystallography of the alpha-hemolysin pore has shown it is a mushroom-shaped, hollow heptamer, almost entirely consisting of beta-structure. Monomeric F subunits have a very similar core structure, except for the transmembrane stem domain which has to refold during pore formation. Large deletions in this domain abolished activity, whereas shorter deletions sometimes improved it, possibly by removing some of the interactions stabilizing the folded structure. Even before stem extension is completed, the formation of an oligomeric pre-pore can trigger Ca(2+)-mediated activation of some white cells, initiating an inflammatory response. Within the bicomponent toxins, gamma-hemolysins define three proteins (HlgA, HlgB, HlgC) that can generate two toxins: HlgA+HlgB and HlgC+HlgB. Like alpha-hemolysin they form pores in planar bilayers with similar conductance, but opposite selectivity (cation instead of anion) for the presence of negative charges in the ion pathway. gamma-Hemolysin pores seem to be organized as alpha-hemolysin, but should contain an even number of each component, alternating in a 1:1 stoichiometry.
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CNR-ITC Istituto di Biofisica, Sezione di Trento, Via Sommarive 18, I-38050 Povo, Italy. menes@itc.it
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Werner
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D000818:Animals; D001427:Bacterial Toxins / Q000737:chemistry*; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D018360:Crystallography, X-Ray; D017353:Gene Deletion; D006460:Hemolysin Proteins / Q000737:chemistry; D006801:Humans; D007249:Inflammation; D007473:Ion Channels / Q000737:chemistry* / Q000378:metabolism; D007477:Ions; D008958:Models, Molecular; D009154:Mutation; D009995:Osmosis; D018272:Porins / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011817:Rabbits; D013211:Staphylococcus aureus / Q000378:metabolism*
D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D007473:Ion Channels; D007477:Ions; D018272:Porins; D002118:Calcium