anthrax lethal factor
Anthrax is an infectious disease caused by the spore-forming bacterium, Bacillus anthracis. Anthrax normally occurs in wild and domesticated animals but it can also infect humans through the use of products from infected animals (cutaneous anthrax), inhalation of anthrax spores from contaminated animal products (inhalation anthrax) and the consumption of undercooked meat from infected animals (intestinal anthrax). Anthrax can be fatal if it is not diagnosed early and is left untreated. Inhalation anthrax is usually fatal, whereas intestinal anthrax results in death in 25-60% of the cases. Bacillus anthracis has two major virulence factors, a poly-D-glutamic acid capsule and anthrax toxin. Lethal Factor (LF) is a protein that functions with two other enzymes, oedema factor and protective antigen (PA), to form the anthrax toxin. LF acts in the host cell by cleaving proteins that are members of the mitogen-activated protein kinase kinase (MAPKK) family near their amino termini with high specificity, resulting in the inhibition of one or more signaling pathways. LF is a potential target for therapeutic agents to inhibit its activity, either by disrupting its active site or by preventing its binding to PA.
The structure here shows a dimer of LF. Each monomer contains 4 domains. Domain I binds PA, which is the membrane-translocating component of the anthrax toxin. Domains II, III and IV form the long deep groove that holds the MAPKK N-terminal tail prior to cleavage. Domain IV coordinates a zinc ion and contains the catalytic site. Domain III structurally resembles Domain II, while Domain IV resembles Domain I. As a result, the authors suggest that the high specificity of LF for MAPKK has evolved through gene duplication, mutation and fusion events.
Protein Data Bank (PDB)
Pannifer, A.D. Wong, T.Y. Schwarzenbacher, R. Renatus, M. Petosa, C. Bienkowska, J. Lacy, D.B. Collier, R.J. Park, S. Leppla, S.H. Hanna, P. Liddington, R.C.; "Crystal structure of the anthrax lethal factor."; Nature; (2001) 414:229-233 PubMed:11700563.
author: Ashwini Patil