title: Crystal structure of the anthrax lethal factor.
abstract: Lethal factor (LF) is a protein (relative molecular mass 90,000) that is critical in the pathogenesis of anthrax. It is a highly specific protease that cleaves members of the mitogen-activated protein kinase kinase (MAPKK) family near to their amino termini, leading to the inhibition of one or more signalling pathways. Here we describe the crystal structure of LF and its complex with the N terminus of MAPKK-2. LF comprises four domains: domain I binds the membrane-translocating component of anthrax toxin, the protective antigen (PA); domains II, III and IV together create a long deep groove that holds the 16-residue N-terminal tail of MAPKK-2 before cleavage. Domain II resembles the ADP-ribosylating toxin from Bacillus cereus, but the active site has been mutated and recruited to augment substrate recognition. Domain III is inserted into domain II, and seems to have arisen from a repeated duplication of a structural element of domain II. Domain IV is distantly related to the zinc metalloprotease family, and contains the catalytic centre; it also resembles domain I. The structure thus reveals a protein that has evolved through a process of gene duplication, mutation and fusion, into an enzyme with high and unusual specificity.
authors.affiliation: Biochemistry Department, University of Leicester, Leicester LE1 7RH, UK.
authors.forename: A D
authors.initials: AD
authors.lastname: Pannifer
authors.forename: T Y
authors.initials: TY
authors.lastname: Wong
authors.forename: R
authors.initials: R
authors.lastname: Schwarzenbacher
authors.forename: M
authors.initials: M
authors.lastname: Renatus
authors.forename: C
authors.initials: C
authors.lastname: Petosa
authors.forename: J
authors.initials: J
authors.lastname: Bienkowska
authors.forename: D B
authors.initials: DB
authors.lastname: Lacy
authors.forename: R J
authors.initials: RJ
authors.lastname: Collier
authors.forename: S
authors.initials: S
authors.lastname: Park
authors.forename: S H
authors.initials: SH
authors.lastname: Leppla
authors.forename: P
authors.initials: P
authors.lastname: Hanna
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* / Q000378:metabolism; D018360:Crystallography, X-Ray; D048370:MAP Kinase Kinase 2; D046911:Macromolecular Substances; D020929:Mitogen-Activated Protein Kinase Kinases / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism; D015032:Zinc / Q000737:chemistry
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D046911:Macromolecular Substances; C030325:anthrax toxin; D011505:Protein-Tyrosine Kinases; D048370:MAP Kinase Kinase 2; D020929:Mitogen-Activated Protein Kinase Kinases; D015032:Zinc