Structural Biochemistry - CNRS URA 2185  


  HEADProf. ALZARI Pedro / alzari@pasteur.fr
  MEMBERSDr ANDRE-LEROUX Gwénaëlle / ARBOGAST Laurence / BARILONE Nathalie / Dr BELLINZONI Marco / Dr BETTON Jean-Michel / FRAYSSE Jocelyne / Dr MARTINEZ Mariano / Dr MECHALY Ariel / SASSOON-CLAVIER Nathalie / Dr SCHAEFFER Francis / SUBRINI Orso / TELLO-MANIGNE Diana / WAGNER Tristan


  Annual Report

Our research activities are oriented towards the biochemical, biophysical and structural studies of proteins involved in microbial physiology and pathogenesis, with a particular focus on bacterial cell signaling mechanisms. Some ongoing projects are described below; additional information can be found in our Web page: http://www.pasteur.fr/recherche/unites/Bstruct.

Ser/Thr phosphorylation in mycobacteria (M. Bellinzoni, G. André-Leroux, P.M. Alzari) Eukaryotic-like Ser/Thr protein kinases and phosphatases play important physiological roles in mycobacteria, but the underlying molecular mechanisms and signal transduction pathways are still poorly understood. Our research is focused on (1) investigating the mode of action of Ser/Thr protein kinases in Mycobacterium tuberculosis, and (2) elucidating phosphodependent signaling pathways that control central metabolism and cell division in mycobacteria, with the specific goal of identifying new drug targets for potential therapeutic applications.

Bacterial regulation of lipid biosynthesis (F. Schaeffer, P.M. Alzari) Bacterial cells exert exquisite control over the biosynthesis of membrane lipids, but the underlying mechanisms are largely unknown. In many Gram-positive bacteria, the expression of genes coding for essential components of the fatty acid synthase system (FAS II) and some of the first steps of phospholipid biosynthesis is controlled by FapR, a global transcriptional repressor. We have previously showed that the DNA binding activity of this represor is itself subject to a unique feed-forward regulation by malonyl-CoA, an essential intermediate of fatty acid biosynthesis. We are carrying out structural and thermodynamic studies of FapR-effector/operator complexes complemented with genetic studies in the model organism Bacillus subtilis and the human pathogen Staphylococcus aureus, in order to understand the molecular mechanisms of FapR and validate this homeostatic pathway as a potential therapeutic target.

Protein folding and secretion mechanisms in bacteria (J.M. Betton) Our group studies bacterial quality control systems for the development of more efficient protein expression processes. If they escape the cellular quality-control systems, proteins may aggregate when E. coli cells are exposed to environmental stress or overexpress recombinant genes (protein factories). Current projects include the study of the CpxA/R signal transduction system, which senses perturbations in the periplasm and responds by up-regulating several protein folding and degrading activities.

Keywords: Mycobacterium tuberculosis,bacterial signaling, protein kinases and phosphatases,two-component systems, regulation of lipid biosynthesis, drug design, bacterial protein expression, X-ray crystallography, microcalorimetry, structural biology



  Publications

Bellinzoni M, Wehenkel A, Shepard W, Alzari PM. (2007) Insights into the catalytic mechanism of PPM Ser/Thr phosphatases from the atomic resolution structures of a mycobacterial enzyme. Structure 15:863-872.

O'Hare H, Duran R, Cervenansky C, Bellinzoni M, Wehenkel A, Pritsch O, Obal G, Baumgartner J, Vialaret J, Johnsson K, Alzari PM. (2008) Regulation of glutamate metabolism by protein kinases in mycobacteria. Mol. Microbiol. 70:1408-1423.

Hindie V, Stroba A, Zhang H, Lopez-Garcia LA, Idrissova L, Zeuzem S, Hirschberg D, Schaeffer F, Jorgensen JD, Engel M, Alzari PM, Biondi RM. (2009) Structure and allosteric effects of low molecular-weight activators on the protein kinase PDK1. Nature Chem. Biol. 5:758-764.

Bellinzoni M, Buroni S, Schaeffer F, Riccardi G, De Rossi E, Alzari PM. (2009) Structural plasticity and distinct drug-binding modes of LfrR, a mycobacterial efflux pump regulator. J. Bacteriol. 191:7531-7537.

Albanesi D, Martin M, Trajtenberg F, Mansilla MC, Haouz A, Alzari PM, de Mendoza D, Buschiazzo A. (2009) Structural plasticity and catalysis regulation of a thermosensor histidine kinase. Proc. Natl. Acad. Sci. USA 106:16185-16190.\





Activity Reports 2010 - Institut Pasteur
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