Anthrax protective antigen forms oligomers during intoxication of mammalian cells.

Milne, Jill C.; Furlong, Dierdre; Hanna, Philip C.; Wall, Joseph S.; Collier, R. J.

doi:10.1016/s0021-9258(17)32036-7

Cited by 377 publications

(82 citation statements)

References 36 publications

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“…Interaction of LF and EF with PA63 occurs at the cell surface after heptamerization has occurred (Singh et al, 1994;Mogridge et al, 2001;. The complex of PA63 with LF and/or EF is then internalized and transported to endosomes where the low pH triggers membrane insertion of the PA63 heptamer and channel formation (Milne et al, 1994;Mourez et al, 2002). Delivery of EF and LF to the cytosol is concomitant with PA63 channel formation and may involve passage of these proteins through the channel.…”

Section: Introductionmentioning

confidence: 99%

Anthrax toxin triggers endocytosis of its receptor via a lipid raft–mediated clathrin-dependent process

Abrami

Liu

Cosson

et al. 2003

The Journal of Cell Biology

450

456

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The protective antigen (PA) of the anthrax toxin binds to a cell surface receptor and thereby allows lethal factor (LF) to be taken up and exert its toxic effect in the cytoplasm. Here, we report that clustering of the anthrax toxin receptor (ATR) with heptameric PA or with an antibody sandwich causes its association to specialized cholesterol and glycosphingolipid-rich microdomains of the plasma membrane (lipid rafts). We find that although endocytosis of ATR is slow, clustering it into rafts either via PA heptamerization or using an antibody sandwich is necessary and sufficient to trigger efficient internalization and allow delivery of LF to the cytoplasm. Importantly, altering raft integrity using drugs prevented LF delivery and cleavage of cytosolic MAPK kinases, suggesting that lipid rafts could be therapeutic targets for drugs against anthrax. Moreover, we show that internalization of PA is dynamin and Eps15 dependent, indicating that the clathrin-dependent pathway is the major route of anthrax toxin entry into the cell. The present work illustrates that although the physiological role of the ATR is unknown, its trafficking properties, i.e., slow endocytosis as a monomer and rapid clathrin-mediated uptake on clustering, make it an ideal anthrax toxin receptor.

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Section: Introductionmentioning

confidence: 99%

Anthrax toxin triggers endocytosis of its receptor via a lipid raft–mediated clathrin-dependent process

Abrami

Liu

Cosson

et al. 2003

The Journal of Cell Biology

450

456

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“…Thus, LST-35 has 10-to 40-foldlower affinity for the PA receptor. Because PA must form a heptamer as part of the intoxication process (15,21), a 10-foldlower affinity for receptor could cause a decrease in toxicity that is much greater than 10-fold, theoretically even approaching 10 7 -fold. This may explain the lack of toxicity of LST-35.…”

Section: Discussionmentioning

confidence: 99%

“…PA is cleaved by a furin-like protease (14) and undergoes receptor-mediated endocytosis (8,10). The PA oligomerizes to form a pore-like heptameric structure (15,21) and transfers LF and EF into the cytosol, where LF and EF induce cytotoxic events (15,16). The combination of LF and PA, known as lethal toxin (LT), lyses mouse macrophages within 90 min after addition of the toxin (8,11).…”

mentioning

confidence: 99%

Identification of a Receptor-Binding Region within Domain 4 of the Protective Antigen Component of Anthrax Toxin

Varughese¹,

Teixeira²,

Liu³

et al. 1999

Infect. Immun.

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Anthrax toxin from Bacillus anthracis is a three-component toxin consisting of lethal factor (LF), edema factor (EF), and protective antigen (PA). LF and EF are the catalytic components of the toxin, whereas PA is the receptor-binding component. To identify residues of PA that are involved in interaction with the cellular receptor, two solvent-exposed loops of domain 4 of PA (amino acids [aa] 679 to 693 and 704 to 723) were mutagenized, and the altered proteins purified and tested for toxicity in the presence of LF. In addition to the intended substitutions, novel mutations were introduced by errors that occurred during PCR. Substitutions within the large loop (aa 704 to 723) had no effect on PA activity. A mutated protein, LST-35, with three substitutions in the small loop (aa 679 to 693), bound weakly to the receptor and was nontoxic. A mutated protein, LST-8, with changes in three separate regions did not bind to receptor and was nontoxic. Toxicity was greatly decreased by truncation of the C-terminal 3 to 5 aa, but not by their substitution with nonnative residues or the extension of the terminus with nonnative sequences. Comparison of the 28 mutant proteins described here showed that the large loop (aa 704 to 722) is not involved in receptor binding, whereas residues in and near the small loop (aa 679 to 693) play an important role in receptor interaction. Other regions of domain 4, in particular residues at the extreme C terminus, appear to play a role in stabilizing a conformation needed for receptor-binding activity.

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“…Anthrax toxin is a binary toxin composed of the binding subunit protective antigen (PA), which can interact with two possible enzymatically active A subunits, lethal factor (LF) and edema factor (EF). PA is enzymatically activated via furin cleavage, and thereupon, the 63 kDa-sized monomers (PA63) can form a hepta-or octameric translocase channel [64,65]. The PA63 monomers have an extended β-hairpin structure, which is also found in Plx2B and C3larvinB (Figure 4).…”

Section: C3-like Toxins With B-subunitsmentioning

confidence: 99%

The Buzz about ADP-Ribosylation Toxins from Paenibacillus larvae, the Causative Agent of American Foulbrood in Honey Bees

Ebeling

Fünfhaus

Genersch

2021

Toxins

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The Gram-positive, spore-forming bacterium Paenibacillus larvae is the etiological agent of American Foulbrood, a highly contagious and often fatal honey bee brood disease. The species P. larvae comprises five so-called ERIC-genotypes which differ in virulence and pathogenesis strategies. In the past two decades, the identification and characterization of several P. larvae virulence factors have led to considerable progress in understanding the molecular basis of pathogen-host-interactions during P. larvae infections. Among these virulence factors are three ADP-ribosylating AB-toxins, Plx1, Plx2, and C3larvin. Plx1 is a phage-born toxin highly homologous to the pierisin-like AB-toxins expressed by the whites-and-yellows family Pieridae (Lepidoptera, Insecta) and to scabin expressed by the plant pathogen Streptomyces scabiei. These toxins ADP-ribosylate DNA and thus induce apoptosis. While the presumed cellular target of Plx1 still awaits final experimental proof, the classification of the A subunits of the binary AB-toxins Plx2 and C3larvin as typical C3-like toxins, which ADP-ribosylate Rho-proteins, has been confirmed experimentally. Normally, C3-exoenzymes do not occur together with a B subunit partner, but as single domain toxins. Interestingly, the B subunits of the two P. larvae C3-like toxins are homologous to the B-subunits of C2-like toxins with striking structural similarity to the PA-63 protomer of Bacillus anthracis.

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Anthrax protective antigen forms oligomers during intoxication of mammalian cells.

Cited by 377 publications

References 36 publications

Anthrax toxin triggers endocytosis of its receptor via a lipid raft–mediated clathrin-dependent process

Anthrax toxin triggers endocytosis of its receptor via a lipid raft–mediated clathrin-dependent process

Identification of a Receptor-Binding Region within Domain 4 of the Protective Antigen Component of Anthrax Toxin

The Buzz about ADP-Ribosylation Toxins from Paenibacillus larvae, the Causative Agent of American Foulbrood in Honey Bees

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