Crystal structure of the anthrax lethal factor

Andrew D. Pannifer, Thiang Yian Wong, Robert Schwarzenbacher, Martin Renatus, Carlo Petosa, Jadwiga Bienkowska, D. Borden Lacy, R. John Collier, Sukjoon Park, Stephen H. Leppla, Philip Hanna and Robert C. Liddington ()
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Andrew D. Pannifer: University of Leicester
Thiang Yian Wong: The Burnham Institute
Robert Schwarzenbacher: The Burnham Institute
Martin Renatus: The Burnham Institute
Carlo Petosa: University of Leicester
Jadwiga Bienkowska: Dana Farber Cancer Institute
D. Borden Lacy: Harvard Medical School
R. John Collier: Harvard Medical School
Sukjoon Park: National Institute of Dental and Craniofacial Research, National Institutes of Health
Stephen H. Leppla: National Institute of Dental and Craniofacial Research, National Institutes of Health
Philip Hanna: University of Michigan Medical School, 5641 Medical Science II
Robert C. Liddington: The Burnham Institute

Nature, 2001, vol. 414, issue 6860, 229-233

Abstract: Abstract Lethal factor (LF) is a protein (relative molecular mass 90,000) that is critical in the pathogenesis of anthrax1,2,3. 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 pathways4,5,6. 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.

Date: 2001
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DOI: 10.1038/n35101998

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