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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.

No MeSH data available.


Ordered and random lethal toxin translocation mechanisms. The presumed stabilizing contacts between adjacent LFs may dictate order that the individual LFs translocate. Shown are possible translocation pathways, where the PA heptamer is colored blue and LF is colored magenta. The ordered mechanism translocates the least encumbered LF first (LF1). This translocation is followed by LF2 and then LF3 in an ordered pathway. The random mechanism translocates the three LFs in any order. Shown are three of the six possible random pathways.
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fig2: Ordered and random lethal toxin translocation mechanisms. The presumed stabilizing contacts between adjacent LFs may dictate order that the individual LFs translocate. Shown are possible translocation pathways, where the PA heptamer is colored blue and LF is colored magenta. The ordered mechanism translocates the least encumbered LF first (LF1). This translocation is followed by LF2 and then LF3 in an ordered pathway. The random mechanism translocates the three LFs in any order. Shown are three of the six possible random pathways.

Mentions: 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. Fabre et al. (2016) speculate further that channel state stabilization, created by contacts between neighboring LFs, might dictate the mechanism by which LF is translocated through the channel. Specifically, they propose a mechanism that would affect the order in which the LF domains translocate through the PA channel (Fig. 2). 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. But this slower rate is not insurmountable, as demonstrated by experiments on the PA8–LF4 complex (Kintzer et al., 2009). Here, only stabilized LFs would be available for the first translocation event because, unlike the heptamer, LFs would make head to tail contacts all the way around the ring of the octamer (Fig. 1, inset). We know from experiments that LFs in the octamer translocate efficiently (Kintzer et al., 2009). Therefore, in support of the “random” translocation mechanism, the most stabilized LF is able to translocate first in the octameric lethal toxin complexes.


Anthrax lethal toxin co-complexes are stabilized by contacts between adjacent lethal factors
Ordered and random lethal toxin translocation mechanisms. The presumed stabilizing contacts between adjacent LFs may dictate order that the individual LFs translocate. Shown are possible translocation pathways, where the PA heptamer is colored blue and LF is colored magenta. The ordered mechanism translocates the least encumbered LF first (LF1). This translocation is followed by LF2 and then LF3 in an ordered pathway. The random mechanism translocates the three LFs in any order. Shown are three of the six possible random pathways.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5037347&req=5

fig2: Ordered and random lethal toxin translocation mechanisms. The presumed stabilizing contacts between adjacent LFs may dictate order that the individual LFs translocate. Shown are possible translocation pathways, where the PA heptamer is colored blue and LF is colored magenta. The ordered mechanism translocates the least encumbered LF first (LF1). This translocation is followed by LF2 and then LF3 in an ordered pathway. The random mechanism translocates the three LFs in any order. Shown are three of the six possible random pathways.
Mentions: 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. Fabre et al. (2016) speculate further that channel state stabilization, created by contacts between neighboring LFs, might dictate the mechanism by which LF is translocated through the channel. Specifically, they propose a mechanism that would affect the order in which the LF domains translocate through the PA channel (Fig. 2). 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. But this slower rate is not insurmountable, as demonstrated by experiments on the PA8–LF4 complex (Kintzer et al., 2009). Here, only stabilized LFs would be available for the first translocation event because, unlike the heptamer, LFs would make head to tail contacts all the way around the ring of the octamer (Fig. 1, inset). We know from experiments that LFs in the octamer translocate efficiently (Kintzer et al., 2009). Therefore, in support of the “random” translocation mechanism, the most stabilized LF is able to translocate first in the octameric lethal toxin complexes.

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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.