Atomic Structures of Anthrax Prechannel Bound with Full-Length Lethal and Edema Factors

Zhou, Kang; Liu, Shiheng; Hardenbrook, Nathan J.; Cui, Yanxiang; Krantz, Bryan A.; Zhou, Zhenqi

doi:10.1016/j.str.2020.05.009

Cited by 9 publications

(19 citation statements)

References 48 publications

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“…Our results support previous findings showing that the D4 domain is highly flexible (Antoni et al, 2020;Zhou et al, 2020). The flexibility of the D4 domain is likely crucial for its role in mediating the interaction of the rigid prepore ring with the cell receptors, which are not Structural mechanism for neutralization of the anthrax toxin by cAb29.…”

Section: Discussionsupporting

confidence: 90%

“…1). The D4 domains are the least-resolved segments of PA in our map, similar to previously determined cryo-EM structures of PA (Antoni et al, 2020;Zhou et al, 2020). The lower resolution of the D4 domain is likely due to its high flexibility, suggesting that the binding of cAb29 did not alter its flexibility.…”

Section: The Overall Structure Of the Pa-cab29 Complexsupporting

confidence: 83%

“…After proteolytic activation by the proteases of the host, the PA chains self-assemble, forming the prepore ring-like oligomer, which consists of 7-8 subunits (Kintzer et al, 2009;Feld et al, 2010;Lacy et al, 2004). The prepore recruits the LF and EF and mediates the transfer of the toxin into the cell by docking on the cell-surface receptors of the host, followed by endocytosis (Mogridge et al, 2002;Lacy et al, 2004;Zhou et al, 2020;Santelli et al, 2004;Antoni et al, 2020). Upon endosome acidification the prepore undergoes a cooperative structural transition, forming an elongated -barrel hose-like structure that opens a pore in the membrane of the endosome.…”

Section: Introductionmentioning

confidence: 99%

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Neutralization of the anthrax toxin by antibody-mediated stapling of its membrane-penetrating loop

Hoelzgen¹,

Zalk²,

Alcalay³

et al. 2021

Acta Cryst Sect D Struct Biol

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Anthrax infection is associated with severe illness and high mortality. Protective antigen (PA) is the central component of the anthrax toxin, which is one of two major virulence factors of Bacillus anthracis, the causative agent of anthrax disease. Upon endocytosis, PA opens a pore in the membranes of endosomes, through which the cytotoxic enzymes of the toxin are extruded. The PA pore is formed by a cooperative conformational change in which the membrane-penetrating loops of PA associate, forming a hydrophobic rim that pierces the membrane. Due to its crucial role in anthrax progression, PA is an important target for monoclonal antibody-based therapy. cAb29 is a highly effective neutralizing antibody against PA. Here, the cryo-EM structure of PA in complex with the Fab portion of cAb29 was determined. It was found that cAb29 neutralizes the toxin by clamping the membrane-penetrating loop of PA to the static surface-exposed loop of the D3 domain of the same subunit, thereby preventing pore formation. These results provide the structural basis for the antibody-based neutralization of PA and bring into focus the membrane-penetrating loop of PA as a target for the development of better anti-anthrax vaccines.

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Section: Discussionsupporting

confidence: 90%

Section: The Overall Structure Of the Pa-cab29 Complexsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

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Neutralization of the anthrax toxin by antibody-mediated stapling of its membrane-penetrating loop

Hoelzgen¹,

Zalk²,

Alcalay³

et al. 2021

Acta Cryst Sect D Struct Biol

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“…Thus, the rough position of the loop's central segment, i.e., towards the D4 domain and the inter-subunit cleft, or the D3 domain and the solvent can be deduced even when this central segment of the D2L2 loop is missing. Based on this approach, we analyzed all the PDB structures of PA in the prepore and monomeric states [4,[8][9][10][18][19][20][21][22][23][24] and compared the orientations of the stems of the D2L2 loops in all of these structures. In some of these structures, the stems are not resolved past the main hinges and therefore they do not provide any clues regarding the position of the loops' central segment (Figure S4b gray).…”

Section: The Conformation Of the Membrane Penetrating Loop In Various Structuresmentioning

confidence: 99%

“…After the proteolytic activation by the host's proteases, the PA chains self-assemble forming the prepore ring-like oligomer which consists of 7-8 subunits [4][5][6]. The prepore recruits the LF and EF and mediates the toxin's transfer into the cell by docking on the host's cell surface receptors, followed by endocytosis [4,[7][8][9][10]. Upon endosome acidification, the prepore undergoes a cooperative structural transition forming an elongated beta-barrel hose-like structure that opens a pore in the endosome's membrane.…”

Section: Introductionmentioning

confidence: 99%

Neutralization of the anthrax toxin by antibody-mediated stapling of its membrane penetrating loop

Hoelzgen

Zalk

Alcalay

et al. 2021

Preprint

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Anthrax infection is associated with severe illness and high mortality. Protective antigen (PA) is the central component of the anthrax toxin, which is the main virulent factor of anthrax. Upon endocytosis, PA opens a pore in the membranes of endosomes, through which the toxin's cytotoxic enzymes are extruded. The PA pore is formed by a cooperative conformational change where PA's membrane-penetrating loops associate, forming a hydrophobic rim that pierces the membrane. Due to its crucial role in anthrax progression, PA is an important target of monoclonal antibodies-based therapy. cAb29 is a highly effective neutralizing antibody against PA. We determined the cryo-EM structure of PA in complex with the Fab portion of cAb29. We found that cAb29 neutralizes the toxin by clamping the membrane-penetrating loop of PA to a static region on PA's surface, thereby preventing pore formation. Therefore, our results provide the structural basis for the antibody-based neutralization of PA and bring to focus the membrane-penetrating loop of PA as a target for the development of better anti-anthrax vaccines.

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Assembly and Function of the Anthrax Toxin Protein Translocation Complex

Liddington¹

2020

Subcellular Biochemistry

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Atomic Structures of Anthrax Prechannel Bound with Full-Length Lethal and Edema Factors

Cited by 9 publications

References 48 publications

Neutralization of the anthrax toxin by antibody-mediated stapling of its membrane-penetrating loop

Neutralization of the anthrax toxin by antibody-mediated stapling of its membrane-penetrating loop

Neutralization of the anthrax toxin by antibody-mediated stapling of its membrane penetrating loop

Assembly and Function of the Anthrax Toxin Protein Translocation Complex

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