title: Crystal structure of the anthrax toxin protective antigen.
abstract: Protective antigen (PA) is the central component of the three-part protein toxin secreted by Bacillus anthracis, the organism responsible for anthrax. After proteolytic activation on the host cell surface, PA forms a membrane-inserting heptamer that translocates the toxic enzymes, oedema factor and lethal factor, into the cytosol. PA, which has a relative molecular mass of 83,000 (M(r) 83K), can also translocate heterologous proteins, and is being evaluated for use as a general protein delivery system. Here we report the crystal structure of monomeric PA at 2.1 A resolution and the water-soluble heptamer at 4.5 A resolution. The monomer is organized mainly into antiparallel beta-sheets and has four domains: an amino-terminal domain (domain 1) containing two calcium ions and the cleavage site for activating proteases; a heptamerization domain (domain 2) containing a large flexible loop implicated in membrane insertion; a small domain of unknown function (domain 3); and a carboxy-terminal receptor-binding domain (domain 4). Removal of a 20K amino-terminal fragment from domain 1 allows the assembly of the heptamer, a ring-shaped structure with a negatively charged lumen, and exposes a large hydrophobic surface for binding the toxic enzymes. We propose a model of pH-dependent membrane insertion involving the formation of a porin-like, membrane-spanning beta-barrel.
authors.affiliation: Biochemistry Department, University of Leicester, UK.
authors.forename: C
authors.initials: C
authors.lastname: Petosa
authors.forename: R J
authors.initials: RJ
authors.lastname: Collier
authors.forename: K R
authors.initials: KR
authors.lastname: Klimpel
authors.forename: S H
authors.initials: SH
authors.lastname: Leppla
authors.forename: R C
authors.initials: RC
authors.lastname: Liddington
mesh_terms: D000595:Amino Acid Sequence; D000942:Antigens, Bacterial; D001408:Bacillus anthracis / Q000737:chemistry; D001427:Bacterial Toxins / Q000737:chemistry* / Q000633:toxicity; D001665:Binding Sites; D002462:Cell Membrane; D018360:Crystallography, X-Ray; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin