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Crystal structure of the anthrax lethal factor

Author

Listed:
  • Andrew D. Pannifer

    (University of Leicester
    AstraZeneca)

  • Thiang Yian Wong

    (The Burnham Institute)

  • Robert Schwarzenbacher

    (The Burnham Institute)

  • Martin Renatus

    (The Burnham Institute)

  • Carlo Petosa

    (University of Leicester
    EMBL Grenoble Outstation)

  • Jadwiga Bienkowska

    (Dana Farber Cancer Institute
    Boston University)

  • 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)

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.

Suggested Citation

  • 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, 2001. "Crystal structure of the anthrax lethal factor," Nature, Nature, vol. 414(6860), pages 229-233, November.
    • Handle: RePEc:nat:nature:v:414:y:2001:i:6860:d:10.1038_n35101998
    DOI: 10.1038/n35101998
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    Cited by:

    1. Philippe Thullier & Arnaud Avril & Jacques Mathieu & Christian K Behrens & Jean-Luc Pellequer & Thibaut Pelat, 2013. "Mapping the Epitopes of a Neutralizing Antibody Fragment Directed against the Lethal Factor of Bacillus anthracis and Cross-Reacting with the Homologous Edema Factor," PLOS ONE, Public Library of Science, vol. 8(5), pages 1-13, May.

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