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Anthrax lethal factor-cleavage products of MAPK (mitogen-activated protein kinase) kinases exhibit reduced binding to

A Jane Bardwell1, Mahsa Abdollahi, Lee Bardwell

  • 1Department of Developmental and Cell Biology, 2208 Natural Sciences I, University of California, Irvine, CA 92697, U.S.A.

The Biochemical Journal
|November 18, 2003
PubMed

Insights

Anthrax lethal toxin inhibits cell signaling by targeting MAPK kinases (MKKs/MEKs). The toxin

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Toxicology

Background:

  • Anthrax lethal toxin (LT) is a primary cause of death in systemic anthrax.
  • LT comprises protective antigen (PA) and lethal factor (LF), a metalloprotease.
  • LF cleaves MAPK kinases (MKKs/MEKs), inhibiting MAPK signaling pathways.

Purpose of the Study:

  • To elucidate the mechanism by which LF-mediated cleavage inhibits MAPK signaling.
  • To investigate the effect of LF cleavage on the substrate-binding ability of MKKs/MEKs.

Main Methods:

  • In vitro cleavage assays using LF on various MKKs/MEKs.
  • Analysis of the substrate-binding capacity of LF-cleaved MKKs/MEKs.

Main Results:

  • LF cleaves MEK1, MEK2, MKK3, MKK4, MKK6, and MKK7.
  • The C-terminal cleavage products of these kinases exhibit reduced binding to their MAPK substrates.
  • This impaired substrate binding suggests a common inhibitory mechanism.

Conclusions:

  • LF-induced inhibition of MAPK signaling occurs via impaired substrate binding of cleaved MKKs/MEKs.
  • This finding reveals a conserved mechanism for LT-induced cellular dysfunction.

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