Molecular Info® Copy Right © 2001
Institute of Molecular Development LLC
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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 & ROBERT C. LIDDINGTON
The Nature, November 2001, 414: 229 - 233.
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. The crystal structure of LF and its complex with the N terminus of MAPKK-2 show that 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.
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