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Anthrax lethal toxin co-complexes are stabilized by contacts between adjacent lethal factors

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Anthrax toxin is a three-protein toxin that must first assemble before carrying out its physiological function of menacing its eukaryotic host... The presumed stabilization by LF interactions might also be mechanistically important for stabilizing the channel complex... This stabilization would maintain the integrity of the channel complex with LF as it traffics through the endosomal compartment and minimize the effects of proteolysis within the endosome/lysosome. speculate further that channel state stabilization, created by contacts between neighboring LFs, might dictate the mechanism by which LF is translocated through the channel... In their model, the LF with the least number of stabilizing contacts with neighboring LFs would translocate first, followed by the LF relieved of its contacts with the now translocated LF... Although this model is feasible, an argument can also be made that LFs translocate randomly (Fig. 2)... All LFs have identical N-terminal leader sequences and therefore have identical probabilities of reaching the central pore and being translocated first... Certainly, if the more stabilized LF were to translocate first, then it would translocate slower than the less-well-stabilized LF... We know from experiments that LFs in the octamer translocate efficiently... Another context in which to consider the stability of anthrax toxin complexes is the bloodstream... Recent work has shown that toxin complexes can assemble in the blood, but this assembly pathway is distinct from cell surface assembly... Presumably, neutralizing antibodies to the toxin would need to target these assembled complexes, but to do so they would need to be designed to target accessible epitopes... Depending on the type of lethal toxin complex, different epitopes would present themselves in this context.

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Lethal toxin assembly and translocation mechanism. PA (blue) and LF (magenta) coassemble after PA is proteolytically nicked. The assembled lethal toxin complexes bind to a cell surface receptor (gold) and are endocytosed. The endosome acidifies, transforming the prechannel PA into a membrane-inserted channel. LF unfolds and translocates through the PA channel. (inset) Two possible oligomeric stoichiometries of the lethal toxin co-complex: PA7–LF3 and PA8–LF4. Because two PA subunits create a binding site for each LF, then the PA heptamer contains only three LFs, and the octamer contains four LFs. As a result, for the heptamer, there is an empty half-site, where the LF–LF contacts are interrupted. The octamer, in contrast, forms LF–LF contacts completely around the ring.
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fig1: Lethal toxin assembly and translocation mechanism. PA (blue) and LF (magenta) coassemble after PA is proteolytically nicked. The assembled lethal toxin complexes bind to a cell surface receptor (gold) and are endocytosed. The endosome acidifies, transforming the prechannel PA into a membrane-inserted channel. LF unfolds and translocates through the PA channel. (inset) Two possible oligomeric stoichiometries of the lethal toxin co-complex: PA7–LF3 and PA8–LF4. Because two PA subunits create a binding site for each LF, then the PA heptamer contains only three LFs, and the octamer contains four LFs. As a result, for the heptamer, there is an empty half-site, where the LF–LF contacts are interrupted. The octamer, in contrast, forms LF–LF contacts completely around the ring.

Mentions: Anthrax toxin is a three-protein toxin that must first assemble before carrying out its physiological function of menacing its eukaryotic host. Much has been done, therefore, to study its assembly both in vitro and on cell surfaces. The three proteins that comprise the toxin are protective antigen (PA), lethal factor (LF), and edema factor (EF). Individually, these proteins are nontoxic, but in combination, they produce toxic complexes (Fig. 1). PA plus LF makes lethal toxin and PA plus EF makes edema toxin. To assemble, PA is first nicked by a protease to yield a 20-kD fragment and the 63-kD fragment, PA63 (Blaustein et al., 1989). PA63 fragments then self-assemble into a ring-shaped prechannel heptamer (Milne et al., 1994; Petosa et al., 1997) or octamer (Kintzer et al., 2009), which can bind to either three or four copies of LF/EF, respectively. The toxin complexes are then endocytosed into endosomes that acidify as they mature, causing the prechannel PA oligomer to convert into a membrane-inserted channel. LF and EF then unfold and translocate through this channel into the cytosol of the host cell. There in the cytosol, LF and EF carry out their physiological functions, catalyzing reactions that disrupt the cell. In this issue, Fabre et al. report a new cryo–electron microscopy (cryo-EM) structure of an anthrax lethal toxin co-complex, containing three copies of LF bound to the PA heptamer (PA7–LF3 complex). This new structure adds another level of complexity to our understanding of anthrax toxin assembly.


Anthrax lethal toxin co-complexes are stabilized by contacts between adjacent lethal factors
Lethal toxin assembly and translocation mechanism. PA (blue) and LF (magenta) coassemble after PA is proteolytically nicked. The assembled lethal toxin complexes bind to a cell surface receptor (gold) and are endocytosed. The endosome acidifies, transforming the prechannel PA into a membrane-inserted channel. LF unfolds and translocates through the PA channel. (inset) Two possible oligomeric stoichiometries of the lethal toxin co-complex: PA7–LF3 and PA8–LF4. Because two PA subunits create a binding site for each LF, then the PA heptamer contains only three LFs, and the octamer contains four LFs. As a result, for the heptamer, there is an empty half-site, where the LF–LF contacts are interrupted. The octamer, in contrast, forms LF–LF contacts completely around the ring.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5037347&req=5

fig1: Lethal toxin assembly and translocation mechanism. PA (blue) and LF (magenta) coassemble after PA is proteolytically nicked. The assembled lethal toxin complexes bind to a cell surface receptor (gold) and are endocytosed. The endosome acidifies, transforming the prechannel PA into a membrane-inserted channel. LF unfolds and translocates through the PA channel. (inset) Two possible oligomeric stoichiometries of the lethal toxin co-complex: PA7–LF3 and PA8–LF4. Because two PA subunits create a binding site for each LF, then the PA heptamer contains only three LFs, and the octamer contains four LFs. As a result, for the heptamer, there is an empty half-site, where the LF–LF contacts are interrupted. The octamer, in contrast, forms LF–LF contacts completely around the ring.
Mentions: Anthrax toxin is a three-protein toxin that must first assemble before carrying out its physiological function of menacing its eukaryotic host. Much has been done, therefore, to study its assembly both in vitro and on cell surfaces. The three proteins that comprise the toxin are protective antigen (PA), lethal factor (LF), and edema factor (EF). Individually, these proteins are nontoxic, but in combination, they produce toxic complexes (Fig. 1). PA plus LF makes lethal toxin and PA plus EF makes edema toxin. To assemble, PA is first nicked by a protease to yield a 20-kD fragment and the 63-kD fragment, PA63 (Blaustein et al., 1989). PA63 fragments then self-assemble into a ring-shaped prechannel heptamer (Milne et al., 1994; Petosa et al., 1997) or octamer (Kintzer et al., 2009), which can bind to either three or four copies of LF/EF, respectively. The toxin complexes are then endocytosed into endosomes that acidify as they mature, causing the prechannel PA oligomer to convert into a membrane-inserted channel. LF and EF then unfold and translocate through this channel into the cytosol of the host cell. There in the cytosol, LF and EF carry out their physiological functions, catalyzing reactions that disrupt the cell. In this issue, Fabre et al. report a new cryo–electron microscopy (cryo-EM) structure of an anthrax lethal toxin co-complex, containing three copies of LF bound to the PA heptamer (PA7–LF3 complex). This new structure adds another level of complexity to our understanding of anthrax toxin assembly.

View Article: PubMed Central - HTML - PubMed

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Anthrax toxin is a three-protein toxin that must first assemble before carrying out its physiological function of menacing its eukaryotic host... The presumed stabilization by LF interactions might also be mechanistically important for stabilizing the channel complex... This stabilization would maintain the integrity of the channel complex with LF as it traffics through the endosomal compartment and minimize the effects of proteolysis within the endosome/lysosome. speculate further that channel state stabilization, created by contacts between neighboring LFs, might dictate the mechanism by which LF is translocated through the channel... In their model, the LF with the least number of stabilizing contacts with neighboring LFs would translocate first, followed by the LF relieved of its contacts with the now translocated LF... Although this model is feasible, an argument can also be made that LFs translocate randomly (Fig. 2)... All LFs have identical N-terminal leader sequences and therefore have identical probabilities of reaching the central pore and being translocated first... Certainly, if the more stabilized LF were to translocate first, then it would translocate slower than the less-well-stabilized LF... We know from experiments that LFs in the octamer translocate efficiently... Another context in which to consider the stability of anthrax toxin complexes is the bloodstream... Recent work has shown that toxin complexes can assemble in the blood, but this assembly pathway is distinct from cell surface assembly... Presumably, neutralizing antibodies to the toxin would need to target these assembled complexes, but to do so they would need to be designed to target accessible epitopes... Depending on the type of lethal toxin complex, different epitopes would present themselves in this context.

No MeSH data available.


Related in: MedlinePlus