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| Anthrax lethal factor cleaves the N-terminus of MAPKKs and induces tyrosine/threonine phosphorylation of MAPKs in cultured macrophages |
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| Author(s): Vitale G, Pellizzari R, Recchi C, Napolitani G, Mock M, Montecucco C |
| Source: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Volume: 248 Issue: 3 Pages: 706-711 Published: JUL 30 1998 |
| Times Cited: 215 References: 34 |
| Abstract: Lethal factor (LF) is the major virulence factor produced by Bacillus anthracis. LF is sufficient to cause death in laboratory animals and cytolysis of peritoneal macrophages and macrophage cell lines. LF contains the characteristic zinc binding motif of metalloproteases and indirect evidence suggest that this hydrolytic activity is essential for its cytotoxicity. To identify the substrate(s) of LF, we have used the yeast two-hybrid system, employing a LF inactive mutant as bait. This approach has led to the identification of the MAP kinase kinases (MAPKKs) Mek1 and Mek2 as proteins capable of specific interaction with LF. LF cleaves Mek1 and Mek2 within their N-terminus in vitro and in vivo, hydrolyzing a Pro8-Ile9 and a Pro10-Arg11 peptide bond in Mek1 and Mek2 respectively, The removal of the amino terminus of MAPKKs eliminates the "docking site" for the MAPKs ERK1 and ERK2, which become phosphorylated in cultured macrophages following toxin challenge. The possible implications of these findings for the cytolysis of macrophage cells induced by LF are discussed. These results open the way to the design and screening of specific inhibitors of LF. (C) 1998 Academic Press. |
| Document Type: Article |
| Language: English |
| Reprint Address: Vitale, G (reprint author), Univ Padua, Dipartimento Sci Biomed, Via Trieste 75, I-35121 Padua, Italy |
Addresses:
1. Univ Padua, Dipartimento Sci Biomed, I-35121 Padua, Italy
2. Univ Padua, Ctr CNR Biomembrane, I-35121 Padua, Italy
3. Inst Pasteur, Lab Genet Mol Toxines, CNRS, URA 1858, F-75724 Paris, France |
| Publisher: ACADEMIC PRESS INC, 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA |
| Subject Category: Biochemistry & Molecular Biology; Biophysics |
| IDS Number: 110TP |
| ISSN: 0006-291X |
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