The Effects of Inhibitors Upon Pore Formation by Diphtheria Toxin and Diphtheria Toxin T Domain |
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Authors: | JC Sharpe K Kachel E London |
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Institution: | (1) Department of Biochemistry and Cell Biology SUNY at Stony Brook, NY 11794-5215, USA, US;(2) Department of Chemistry, and the Institute for Cell and Developmental Biology, State University of New York at Stony Brook, Stony Brook, NY 11794-5215, USA, US |
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Abstract: | The formation of pores by membrane-inserted diphtheria toxin is closely linked to the translocation of its catalytic chain
across membranes. In this report a number of aromatic polyanionic molecules were identified that inhibit toxin-induced leakage
of molecules from model membrane vesicles. One inhibitor, Cibacron blue, totally blocked pore formation. Aniline blue and
Fast Green decreased the size of the molecule released by a given concentration of toxin. Amaranth appeared to reduce the
maximal amount of leakage, without greatly affecting the size of the molecule released at a given toxin concentration. Finally,
Ponceau S and Cibacron brilliant red appeared to exhibit a mixture of these various types of inhibition. The inhibitors neither
prevented the conformational transition of the toxin to form a hydrophobic state at low pH, nor (with the exception of Cibacron
Brilliant Red) appeared to strongly inhibit toxin binding to model membranes. Additional experiments showed release of trapped
materials from model membranes by isolated T domain of the toxin was similar to that by whole toxin. The effects of inhibitors
on T domain induced release was also similar to that they have on whole toxin. Therefore, it is likely that the inhibition
of pore formation by whole toxin involves inhibitor interaction with the T domain. The inhibitors identified in this study
may be helpful for development of agents that interfere with toxin action in vivo.
Received: 10 March 1999/Revised: 22 June 1999 |
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Keywords: | : Fluorescence quenching — Membrane insertion — Lipid-protein interaction — Model membranes |
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