Guy Salvesen's Research Focus
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 lead 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.
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 in vivo.
Guy Salvesen's Bio
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.
1981: Ph.D., Cambridge University, England, Biology
1977: B. Sc., London University, London, England, Microbiology
Adjunct Professor, Department of Pathology, University of California, San Diego
Honors and Recognition
2014: Organizer, Keystone Meeting on Cell Death, February
2013: IUBMB Gold Medal Recipient, October
2010: Keynote Speaker, European Cell Death Organization Conference,
2010: Keynote Speaker, Gordon Research Conference on Cell Death
2009: Lifetime Achievement Award of the International Proteolysis Society
2008: Keynote Speaker, Queenstown Molecular Biology Conference
2008: Chair, Gordon Research Conference on Cell Death
2005: Helmut Holzer Memorial Prize
1999: International Proteolysis Society, Elected Secretary
1999: Keynote Speaker, Gordon Research Conference on Matrix Metalloproteinases
1988: American Association for the Study of Liver Diseases, State of the Art Lecture
1996: Chair, Gordon Research Conference on Proteolytic Enzymes and Their Inhibitors
Fasci D, Anania VG, Lill JR, Salvesen GS
Sci Signal 2015 Jun 9 ;8(380):ra56
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):447-457
Drag M, Salvesen GS
Nat Rev Drug Discov 2010 Sep ;9(9):690-701
Evolutionary loss of inflammasomes in the Carnivora and implications for the carriage of zoonotic infections.
Digby Z, Tourlomousis P, Rooney J, Boyle JP, Bibo-Verdugo B, Pickering RJ, Webster SJ, Monie TP, Hopkins LJ, Kayagaki N, Salvesen GS, Warming S, Weinert L, Bryant CE
Cell Rep 2021 Aug 24 ;36(8):109614
Evaluation of the effects of phosphorylation of synthetic peptide substrates on their cleavage by caspase-3 and -7.
Maluch I, Grzymska J, Snipas SJ, Salvesen GS, Drag M
Biochem J 2021 Jun 25 ;478(12):2233-2245
Kasperkiewicz P, Hempel A, Janiszewski T, Kołt S, Snipas SJ, Drag M, Salvesen GS
J Biol Chem 2020 Dec 18 ;295(51):17624-17631
Poreba M, Groborz KM, Rut W, Pore M, Snipas SJ, Vizovisek M, Turk B, Kuhn P, Drag M, Salvesen GS
J Am Chem Soc 2020 Sep 30 ;142(39):16704-16715
Author Correction: Endothelial activation of caspase-9 promotes neurovascular injury in retinal vein occlusion.
Avrutsky MI, Ortiz CC, Johnson KV, Potenski AM, Chen CW, Lawson JM, White AJ, Yuen SK, Morales FN, Canepa E, Snipas S, Salvesen GS, Jean YY, Troy CM
Nat Commun 2020 Jul 9 ;11(1):3502
Design, synthesis, and in vitro evaluation of aza-peptide aldehydes and ketones as novel and selective protease inhibitors.
Corrigan TS, Lotti Diaz LM, Border SE, Ratigan SC, Kasper KQ, Sojka D, Fajtova P, Caffrey CR, Salvesen GS, McElroy CA, Hadad CM, Doğan Ekici Ö
J Enzyme Inhib Med Chem 2020 Dec ;35(1):1387-1402