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GUY SALVESEN, PH.D.
Program Director, Professor
Apoptosis and Cell Death Research
858.646.3114 (phone)
858.795.5274 (fax)
gsalvesen@burnham.org
RESEARCH FOCUS, BIOGRAPHY, STAFF, PUBLICATIONS
Research Focus
The human body contains cells with different life expectancies. Some (white blood cells, skin) are programmed to rapidly die and be replaced. Others (nerve cells) are programmed to survive the lifetime of the individual and are seldom replaced. Dr. Salvesen's research focuses on the central role enzyme pathways play in the life and death of cells. When death pathways slow down in cells that are normally programmed to die, cancer results. Conversely, when death pathways become overactive in cells that are programmed to survive, degenerative disease occurs. Dr. Salvesen's laboratory focuses on understanding the fundamental molecular interactions that occur within these enzyme pathways. This knowledge is used to engineer synthetic compounds to stimulate cell destruction in cancer cells, or delay cell destruction in neurodegenerative diseases and stroke.
Biography
Guy Salvesen earned his Ph.D. in biochemistry from Cambridge University in 1980. He conducted postdoctoral research at Strangeways Laboratory and MRC Laboratory of Molecular Biology in Cambridge, followed by further post-doctoral training at the University of Georgia. In 1991 he was appointed Assistant Professor at Duke University. Dr. Salvesen was recruited to the Burnham Institute for Medical Research in 1996, where he is Director of the Program in Apoptosis and Cell Death Research, and Director of Scientific Training. He also holds an adjunct position as Professor of Pathology at the University of California, San Diego.
Selected Publications
Drag, M., Mikolajczyk, J., Krishnakumar, I. M., Huang, Z. and Salvesen, G. S. (2008) Activity profiling of human deSUMOylating enzymes (SENPs) with synthetic substrates suggests an unexpected specificity of two newly characterized members of the family. Biochem J 409, 461-469
Riedl, S. J. and Salvesen, G. S. (2007) The apoptosome: signalling platform of cell death. Nat Rev Mol Cell Biol 5, 405-413
Mikolajczyk, J., Drag, M., Bekes, M., Cao, J. T., Ronai, Z. and Salvesen, G. S. (2007) Small Ubiquitin-related Modifier (SUMO)-specific Proteases: Profiling The Specificities And Activities Of Human Senps. J Biol Chem 282, 26217-26224
Timmer, J. C., Enoksson, M., Wildfang, E., Zhu, W., Igarashi, Y., Denault, J. B., Ma, Y., Dummitt, B., Chang, Y. H., Mast, A. E., Eroshkin, A., Smith, J., Tao, W. A. and Salvesen, G. S. (2007) Profiling constitutive proteolytic events in vivo. Biochem J 407, 41-48
Pop, C., Timmer, J., Sperandio, S. and Salvesen, G. S. (2006) The apoptosome activates caspase-9 by dimerization. Mol Cell 22, 269-275
Denault, J. B., Bekes, M., Scott, F. L., Sexton, K. M., Bogyo, M. and Salvesen, G. S. (2006) Engineered hybrid dimers: tracking the activation pathway of caspase-7. Mol Cell 23, 523-533
List of Publications via PubMed
(NIH National Library of Medicine)
Research Report
STRUCTURE AND FUNCTION OF PROTEASES AND THEIR NATURAL INHIBITORS
(Download report as PDF)
Our research seeks to deliniate the structure->activity->function algorithm as it applies to proteases and their inhibitors. Our laboratory has very broad interests in principles of proteolysis in humans, and we take multi-pronged approaches to research on proteases and their inhibitors.
Apoptosis
In one approach we apply basic biochemical knowledge to investigate newly emerging principles of proteolysis in human systems. This research is currently directed at dissecting the proteolytic components of the intracellular pathway that leads to apoptotic cell death. Programmed cell death monitors the growth of new cells and the elimination of old ones. This program contains a number of proteolytic steps that are essential for efficient execution of the death pathway. Thus the proteases of the pathway - the caspases - are involved in the normal maintenance of correct cell number, and are therefore implicated in a number of pathologic and physiologic conditions. Using the techniques of protein chemistry, enzymology, crystallography, and recombinant DNA methodologies, we analyze the basic mechanism utilized by the caspases to promote cell death pathways, and the mechanisms and specificity of the natural inhibitors that control them.
The second BIR domain of X-linked Inhibitor of Apoptosis Protein (XIAP-green) binds into the substrate groove of caspase 3, preventing access of a protein substrate and terminating apoptosis. This representation is based on the PDB structure file 1I3O (Riedl et al., Cell, 104, 791-800, 2001).
Cell SignalingModification of proteins by the small ubiquitin-like modifier SUMO is a dynamic and reversible process. The SUMO cycle begins when SUMO precursors are processed to remove short C-terminal extensions, thereby uncapping the C-terminal Gly-Gly motif that is essential for conjugation. SUMO ligases conjugate the protein, via its C-terminal carboxylate, to the side-chain lysine of target proteins to generate an isopeptide linkage. Eventually, SUMO is removed intact from its substrate SUMOylated proteins, and so the SUMOylation/deSUMOylation cycle regulates SUMOs function. A group of proteases known as SENPs are involved in both the activation of SUMO precursors (endopeptidase cleavage) and deconjugation of the targets (isopeptidase cleavage). Our laboratory is currently involved in projects to define the mechanisms that mediate the regulation of SENP activity and access to their natural substrates.
Technology DevelopmentThe principle of proteolysis in vivo is to instigate irreversible changes to a set of protein substrates that alters their function, and generates the required biological event. The sum total of the proteases and their target substrates operating in a physiologic pathway therefore defines the global event. Consequently, the identity of the substrate cleavages defines the proteases acting on them. We are developing proteomics based methodologies, including selective protein labeling, multi-dimensional electrophoresis, and mass spectrometry techniques, to identify the products of proteolysis in vivo.
