Kintzer, A.F. and Sterling, H.J. and Tang, I.I. and Abdul-Gader, Ali and Miles, Andrew J. and Wallace, Bonnie A. and Williams, E. and Krantz, B.A. (2010) Role of the protective Antigen Octamer in the molecular mechanism of Anthrax lethal toxin stabilization in plasma. Journal of Molecular Biology 399 (5), pp. 741-758. ISSN 0022-2836.Full text not available from this repository.
Anthrax is caused by strains of Bacillus anthracis that produce two key virulence factors, anthrax toxin (Atx) and a poly-γ-D-glutamic acid capsule. Atx is comprised of three proteins: protective antigen (PA) and two enzymes, lethal factor (LF) and edema factor (EF). To disrupt cell function, these components must assemble into holotoxin complexes, which contain either a ring-shaped homooctameric or homoheptameric PA oligomer bound to multiple copies of LF and/or EF, producing lethal toxin (LT), edema toxin, or mixtures thereof. Once a host cell endocytoses these complexes, PA converts into a membrane-inserted channel that translocates LF and EF into the cytosol. LT can assemble on host cell surfaces or extracellularly in plasma. We show that, under physiological conditions in bovine plasma, LT complexes containing heptameric PA aggregate and inactivate more readily than LT complexes containing octameric PA. LT complexes containing octameric PA possess enhanced stability, channel-forming activity, and macrophage cytotoxicity relative to those containing heptameric PA. Under physiological conditions, multiple biophysical probes reveal that heptameric PA can prematurely adopt the channel conformation, but octameric PA complexes remain in their soluble prechannel configuration, which allows them to resist aggregation and inactivation. We conclude that PA may form an octameric oligomeric state as a means to produce a more stable and active LT complex that could circulate freely in the blood.
|Additional Information:||*Research student, left 2009 (PR 17.8.11)|
|Keyword(s) / Subject(s):||channel formation, electron microscopy, ion channel electrophysiology, mass spectrometry, synchrotron radation circular dichroism spectroscopy|
|School or Research Centre:||Birkbeck Schools and Research Centres > School of Science > Biological Sciences|
|Date Deposited:||30 Mar 2011 14:44|
|Last Modified:||17 Apr 2013 12:20|
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