Both PA63 and PA83 are endocytosed within an anthrax protective antigen mixed heptamer: a putative mechanism to overcome a furin deficiency.
Anthrax toxin consists of protective antigen (PA), and lethal (LF) and edema (EF) factors. A 83 kDa PA monomer (PA83) precursor binds to the cell receptor. Furin-like proprotein convertases (PCs) cleave PA83 to generate cell-bound 63 kDa protein (PA63). PA63 oligomerizes to form a ring-shaped heptamer that binds LF-EF and facilitates their entry into the cells. Several additional PCs, as opposed to furin alone, are capable of processing PA83. Following the incomplete processing of the available pool of PA83, the functional heptamer includes both PA83 and PA63. The available structures of the receptor-PA complex imply that the presence of either one or two molecules of PA83 will not impose structural limitations on the formation of the heptamer and the association of either the (PA83)(1)(PA63)(6) or (PA83)(2)(PA63)(5) heteroheptamer with LF-EF. Our data point to the intriguing mechanism of anthrax that appears to facilitate entry of the toxin into the cells which express limiting amounts of PCs and an incompletely processed PA83 pool.
Chekanov
Alexei V
AV
Infectious and Inflammatory Disease Center, The Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Remacle
Albert G
AG
Golubkov
Vladislav S
VS
Akatov
Vladimir S
VS
Sikora
Sergey
S
Savinov
Alexei Y
AY
Fugere
Martin
M
Day
Robert
R
Rozanov
Dmitri V
DV
Strongin
Alex Y
AY
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000942:Antigens, Bacterial / Q000378:metabolism*; D001408:Bacillus anthracis / Q000737:chemistry / Q000378:metabolism*; D001427:Bacterial Toxins / Q000378:metabolism*; D001665:Binding Sites; D002478:Cells, Cultured; D019281:Dimerization; D004705:Endocytosis; D045683:Furin / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008970:Molecular Weight; D043484:Proprotein Convertases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D014757:Viper Venoms
D000900:Anti-Bacterial Agents; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D011956:Receptors, Cell Surface; D014757:Viper Venoms; C030325:anthrax toxin; C416405:edema factor; D043484:Proprotein Convertases; D045683:Furin