Role of the protective antigen octamer in the molecular mechanism of anthrax lethal toxin stabilization in plasma.
Role of the protective antigen octamer in the molecular mechanism of anthrax lethal toxin stabilization in plasma.
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DOI：
10.1016/j.jmb.2010.04.041
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发表时间：
2010-06-25
影响因子：
5.6
通讯作者：
Krantz BA
中科院分区：
文献类型：
--
作者：
Kintzer AF;Sterling HJ;Tang II;Abdul-Gader A;Miles AJ;Wallace BA;Williams ER;Krantz BA
炭疽是由炭疽杆菌菌株引起的，该菌株产生两种关键毒力因子，炭疽毒素（Atx）和聚-γ-D-谷氨酸胶囊。Atx由三种蛋白质组成：保护性抗原（PA）和两种酶，致死因子（LF）和水肿因子（EF）。为了破坏细胞功能，这些组分必须组装成全毒素复合物，其含有与LF和/或EF的多个拷贝结合的环状同源八聚体或同源七聚体PA寡聚体，产生致死毒素（LT）、水肿毒素或其混合物。一旦宿主细胞内吞这些复合物，PA转化为膜插入通道，将LF和EF易位到胞质溶胶中。LT可以在宿主细胞表面或细胞外的血浆中组装。我们表明，在生理条件下，在牛血浆中，LT复合物含有七聚体PA的聚集和更容易比LT复合物含有八聚体PA。含有八聚体PA的LT复合物相对于含有七聚体PA的那些具有增强的稳定性、通道形成活性和巨噬细胞毒性。在生理条件下，多个生物物理探针揭示，七聚体PA可以过早地采用通道构象，但八聚体PA复合物保持在其可溶性prechannel配置，使他们能够抵抗聚集和失活。我们得出结论，PA可能会形成一个八聚体的寡聚状态作为一种手段，以产生一个更稳定和活跃的LT复合物，可以在血液中自由循环。
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 either 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 may assemble on host cell surfaces or extracellularly in plasma. We show that under physiological conditions in bovine plasma that 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 allowing 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 may circulate freely in the blood.
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