Cesare MONTECUCCO
Curriculum Vitae
1971: graduated with honours in organic chemistry at the University of Padua with a thesis on solid-phase sequencing of peptides.
1971-73: military service in the Italian Military Navy.
1975: graduated with honours in biological sciences at the University of Padua with a thesis on the structure of the mitochondrial ATP-synthase probed with a spin-labelled carbodiimmide inhibitor.
1976-1977: two years of post-doctoral work supported by a long-term EMBO fellowship at the University of Cambridge in the laboratory of Dr. J.C. Metcalfe studying lipid-protein interactions of the sarcoplasmic reticulum Ca-ATPase probed by 13C-NMR and by spin-labelling.
1977: while in Cambridge started a fruitful collaboration with Drs. R.Y. Tsien and T.J. Rink (Physiological Laboratory) on the mechanism of lymphocyte capping.
1978-83: Assistant Professor at the Institute of General Pathology, School of Medicine, University of Padua. Investigations on the structure and lipid-protein interactions of several multi-subunit membrane-bound enzymes with a set of radioactive photoactivatable lipid analogues, to identity the protein regions exposed to lipids. Investigated the membrane interaction of cholera toxin and proposed a mechanism for its membrane penetration, subsequently confirmed by the 3-D crystal structure.
1983-1986: Associate Professor at the same institution. Research fully devoted to the study of the cellular mechanism of action of cholera toxin, pertussis toxin, diptheria toxin, tetanus and botulinum neurotoxins.
1984: short term EMBO fellowship in the laboratory of Prof. J.P. Changeux at the Institut Pasteur (Paris) to study the membrane organization of the ACh nicotinic receptor.
1986 on: Full Professor of General Pathology in the Faculty of Sciences of the University of Padova. Research continued on the study of the cellular mechanism of action of bacterial toxins with intracellular targets. Proposed the cleft model for the membrane translocation of diphtheria toxin. Proposed the double "protein-and-lipid" model for the binding of tetanus and botulism neurotoxins to nerve terminals. Studied the membrane translocation of diphtheria toxin and of the clostridial neurotoxins. Labelling and identification of active site residues of diphtheria toxin. Proposed the cleft model for the membrane translocation of bacterial protein toxins with intracellular targets.
1990: short-term EMBO fellowship in the laboratory of Prof. B. de Kruijff at the Department of Molecular Biology of the University of Utrecht to study the lipid interaction of diphtheria and tetanus toxin by the lipid monolayer technique and the role of gangliosides as presynaptic receptors.
1991-1994: discovered the zinc-endopeptidase activity of tetanus and botulinum neurotoxins and identified the intraneuronal targets and site of cleavage of VAMP-synaptobrevin, SNAP-25 and syntaxin (SNARE proteins) by these neurotoxins. Provided evidence that the animal resistance to tetanus and botulism type B may be due to mutation of VAMP at the site of proteolytic cleavage. Identified the major determinant in the specific recognition of the three SNARE proteins by the eight clostridial neurotoxins. Elaborated the now widely accepted model that bacterial toxins with intracellular activity enter cells via a four-step mechanism.
1993-2000. Discovered the acid activation of the VacA cytotoxin of H. pylori, the late endosomal/prelysosomal nature of the vacuoles induced by the VacA and determined some immunological and pathological consequences of the alterations of membrane trafficking at the level of late endosomes. Discovered that VacA inhibits antigen processing and the invariant chain dependent antigen presentation and that VacA induces a specific change of the trans-epithelial resistance of epithelial cell monolayers. Demonstrated that these VacA activity are due to the formation of an anion-selective channels. Identified the neutrophil activating protein of H. pylori (HP-NAP) as a major antigen in the human response and determined its structural, biochemical and cell activation properties.
1998-2004: Discovered that the anthrax lethal factor is a zinc-endopeptidase specific for the MAPK-kinases, which are cleaved within their N-terminus, determined the recognition motif and designed synthetic substrates for a high throughput screening of specific inhibitors. First evidence that the lethal factor acts at the very beginning of the infection by inhibiting the macrophage production of cytokines. Identified a very potent inhibitor of the anthrax lethal factor. Demonstration that edema factor and lethal factor act synergistically to block activation and proliferation of T cells.
2000-2004: proposed a novel model for the mechanism of action of snake PLA2 presynaptic neurotoxins and provided experimental evidence.
