The dynamics and mechanism of SUMO chain deconjugation by SUMO-specific proteases.
Békés M, Prudden J, Srikumar T, Raught B, Boddy MN, Salvesen GS
J Biol Chem. 2011 Mar 25;286(12):10238-47
FLIP(L) induces caspase 8 activity in the absence of interdomain caspase 8 cleavage and alters substrate specificity.
Pop C, Oberst A, Drag M, Van Raam BJ, Riedl SJ, Green DR, Salvesen GS
Biochem J. 2011 Feb 1;433(3):447-57
Emerging principles in protease-based drug discovery.
Drag M, Salvesen GS
Nat Rev Drug Discov. 2010 Sep;9(9):690-701
Structural and kinetic determinants of protease substrates.
Timmer JC, Zhu W, Pop C, Regan T, Snipas SJ, Eroshkin AM, Riedl SJ, Salvesen GS
Nat Struct Mol Biol. 2009 Oct;16(10):1101-8
The Fas-FADD death domain complex structure unravels signalling by receptor clustering.
Scott FL, Stec B, Pop C, Dobaczewska MK, Lee JJ, Monosov E, Robinson H, Salvesen GS, Schwarzenbacher R, Riedl SJ
Nature. 2009 Feb 19;457(7232):1019-22
Activity profiling of human deSUMOylating enzymes (SENPs) with synthetic substrates suggests an unexpected specificity of two newly characterized members of the family.
Drag M, Mikolajczyk J, Krishnakumar IM, Huang Z, Salvesen GS
Biochem J. 2008 Jan 15;409(2):461-9
Profiling constitutive proteolytic events in vivo.
Timmer JC, Enoksson M, Wildfang E, Zhu W, Igarashi Y, Denault JB, Ma Y, Dummitt B, Chang YH, Mast AE, Eroshkin A, Smith JW, Tao WA, Salvesen GS
Biochem J. 2007 Oct 1;407(1):41-8
Small ubiquitin-related modifier (SUMO)-specific proteases: profiling the specificities and activities of human SENPs.
Mikolajczyk J, Drag M, Békés M, Cao JT, Ronai Z, Salvesen GS
J Biol Chem. 2007 Sep 7;282(36):26217-24
The apoptosome: signalling platform of cell death.
Riedl SJ, Salvesen GS
Nat Rev Mol Cell Biol. 2007 May;8(5):405-13
Engineered hybrid dimers: tracking the activation pathway of caspase-7.
Denault JB, Békés M, Scott FL, Sexton KM, Bogyo M, Salvesen GS
Mol Cell. 2006 Aug;23(4):523-33
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Expedient Synthesis of Highly Potent Antagonists of Inhibitor of Apoptosis Proteins (IAPs) with Unique Selectivity for ML-IAP.
Vamos M, Welsh K, Finlay D, Lee PS, Mace PD, Snipas SJ, Gonzalez ML, Ganji SR, Ardecky RJ, Riedl SJ, Salvesen GS, Vuori K, Reed JC, Cosford ND
ACS Chem Biol. 2013 Jan 16;
Guy Salvesen's Research Focus
Cancer, Inflammatory/Autoimmune Disease, Neurodegenerative and Neuromuscular Diseases
The human body contains cells with different life expectancies. Some (white blood cells or skin, for example) are programmed to rapidly die and be replaced. Others (such as 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.
Guy Salvesen's Research Report
Structure and Function of Proteases and Their Natural Inhibitors
Our research seeks to delineate 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.
In one approach we apply basic biochemical knowledge to investigate newly emerging principles of proteolysis in human systems. This research is currently 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 caspases to promote cell death pathways, and the mechanisms and specificity of the natural inhibitors that control them.
Caption: 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).
Modification 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 regulate SENP activity and access to their natural substrates.
The 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
About Guy Salvesen
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 Sanford-Burnham Medical Research Institute in 1996, where he is professor and director of the Apoptosis and Cell Death Research Program and dean of the Graduate School of Biomedical Sciences. He also holds an adjunct position as professor in the Department of Pathology at the University of California, San Diego.
Ph. D., University of Georgia, Athens, GA, Biochemistry, 1983
Ph. D., Cambridge University, England, Biology, 1981
B. Sc., London University, London, England, Microbiology, 1977
Adjunct Professor, Department of Pathology, University of California, San Diego
Honors and Recognition
European Cell Death Organization Conference, Keynote Speaker, 2010
Gordon Research Conference on Cell Death, Keynote Speaker, 2010
Lifetime Achievement Award of the International Proteolysis Society, 2009
Queenstown Molecular Biology Conference, Keynote Speaker, 2008
Gordon Research Conference on Cell Death, Chair, 2008
Helmut Holzer Memorial Prize, 2005
International Proteolysis Society, Elected Secretary, 1999
Gordon Research Conference on Matrix Metalloproteinases, Keynote Speaker, 1999
American Association for the Study of Liver Diseases, State of the Art Lecture. 1988
Gordon Research Conference on Proteolytic Enzymes and their Inhibitors, Chair, 1996