Membrane insertion of the heptameric staphylococcal alpha-toxin pore. A domino-like structural transition that is allosterically modulated by the target cell membrane.
Staphylococcal alpha-toxin forms heptameric pores on eukaryotic cells. After binding to the cell membrane in its monomeric form, the toxin first assembles into a heptameric pre-pore. Subsequently, the pre-pore transforms into the final pore by membrane insertion of an amphipathic beta-barrel, which comprises the "central loop" domains of all heptamer subunits. The process of membrane insertion was analyzed here using a set of functionally altered toxin mutants. The results show that insertion may be initiated within an individual protomer when its NH2 terminus activates its central loop. The activated state is then shared with the central loops of the residual heptamer subunits, which results in cooperative membrane penetration. This cooperation of the central loops commences while these are still remote from the lipid bilayer. Nevertheless, it is subject to modulation by the target membrane, which therefore acts across a distance much like an allosteric effector. However, while allosteric transitions usually are reversible, membrane insertion of alpha-toxin is an irreversible event, and we show here that it can proceed to completion in a domino-like fashion when triggered by as little as a single foreign atom within the entire heptamer.
Valeva
A
A
Institute of Medical Microbiology and Hygiene, University of Mainz, Obere Zahlbacher Strasse 67, D55101 Mainz, Germany. avaleva@mail.uni-mainz.de
Schnabel
R
R
Walev
I
I
Boukhallouk
F
F
Bhakdi
S
S
Palmer
M
M
D000494:Allosteric Regulation; D000818:Animals; D001427:Bacterial Toxins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D002462:Cell Membrane / Q000378:metabolism; D017931:DNA Primers; D005347:Fibroblasts / Q000378:metabolism; D006460:Hemolysin Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016296:Mutagenesis; D011817:Rabbits
D001427:Bacterial Toxins; D017931:DNA Primers; D006460:Hemolysin Proteins; C021091:staphylococcal alpha-toxin