Raymond Joseph Deshaies (born September 25, 1961) is an American biochemist and cell biologist. He is a board director or member of the scientific advisory board of several biotechnology companies and professor emeritus at California Institute of Technology (Caltech). Previously, he was distinguished fellow and senior vice president of global research at Amgen. Prior to that, he was a professor of biology at Caltech and an investigator of the Howard Hughes Medical Institute. He is also the co-founder of the biotechnology companies Proteolix and Cleave Biosciences. His research focuses on mechanisms and regulation of protein homeostasis in eukaryotic cells, with a particular focus on how proteins are conjugated with ubiquitin and degraded by the proteasome.
Biography Deshaies was born in Waterbury, Connecticut, on September 25, 1961. He graduated from Cornell University with a B.S. in biochemistry in 1983. He received his biochemistry doctorate from the University of California, Berkeley, in 1988 under the direction of Randy Schekman. He performed postdoctoral studies at Berkeley (1988–1990) and subsequently at the University of California, San Francisco (1990–1994) with Marc Kirschner. He started as an assistant professor at Caltech in 1994.
Scientific contributions Drug development: Deshaies, in collaboration with Craig Crews (Yale), conceived the idea of using heterobifunctional small molecules, referred to as PROTACs, to tether cellular proteins to a ubiquitin ligase, resulting in ubiquitination and degradation of the tethered protein.Sakamoto, K.M., Kim, K.B., Kumagai, A., Mercurio, F., Crews, C.C., and Deshaies, R.J. (2001). Protacs: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc. Natl. Acad. Sci. USA 98, 8554-9 This concept underlaid the launch of numerous biotechnology companies including Arvinas, C4 Therapeutics, and Kymera. The Deshaies group also identified small molecules that inhibit targeting of substrates to the proteasome Verma, R., Peters, N.R., Tochtrop, G.P., Sakamoto, K.M., D’Onofrio, M., Varadan, R., Fushman, D., Deshaies, R.J., and King, R.W. (2004). Ubistatins inhibit proteasome-dependent degradation by binding the ubiquitin chain. Science 306, 117-120 and removal of ubiquitin chains from substrates by Rpn11. In addition, they discovered (in collaboration with Dr. Hugh Rosen of Scripps and Frank Schoenen of University of Kansas) the p97 inhibitors DBeQ Chou, T.F., Brown, S.J., Minond, D., Nordin, B.E., Li, K., Jones, A.C., Chase, P., Porubsky, P.R., Stoltz, B.M., Schoenen, F.J., Patricelli, M.P., Hodder, P., Rosen, H., and Deshaies, R.J. (2011) Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways. Proc. Natl. Acad. Sci. USA 108, 4834-4839 and ML240.Chou, T.F., Li, K., Frankowski, K.J., Schoenen, F.J., and Deshaies, R.J. (2013). Structure-activity relationship study reveals ML240 and ML241 as potent and selective inhibitors of p97 ATPase. Chem. Med. Chem. 8, 297-312 ML240 served as the basis for the development of CB-5083,Anderson, D.J., Le Moigne, R., Djakovic, S., Kumar, B., Rice, J., Wong, S., Wang, J., Yao, B., Valle, E., Kiss von Soly, S., Madriaga, A., Soriano, F., Menon, M.K., Wu, Z.Y., Kampmann, M., Chen, Y., Weissman, J.S., Aftab, B.T., Jakes, F.M., Shawver, L., Zhou, H.J., Wustrow, D., and Rolfe, M. (2015). Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis. Cancer Cell 28, 653-665 which entered human clinical trials in 2014.
Protein translocation: As a graduate student and postdoctoral fellow working with Dr. Randy Schekman at the University of California, Berkeley, Deshaies discovered Sec61, which comprises the heart of the translocon that mediates insertion of secretory and membrane proteins into the endoplasmic reticulum of all eukaryotic cells.Deshaies, R.J., Fish, L.E., and Jagendorf, A.T. (1984). Permeability of chloroplast envelopes to Mg2+. Effects on protein synthesis. Plant Physiol. 74, 956-961Stirling, C.J., Rothblatt, J., Hosobuchi, M., Deshaies, R., and Schekman, R. (1992). Protein translocation mutants defective in the insertion of integral membrane proteins into the endoplasmic reticulum. Mol. Biol. Cell 3, 129-142 He went on to identify a complex of proteins that form the translocon in yeast cells.Deshaies, R.J., Sanders, S., Feldheim, D., and Schekman, R. (1991). Assembly of yeast Sec proteins involved in translocation into the endoplasmic reticulum into a membrane-bound multisubunit complex. Nature 349, 806-808 In addition, Deshaies discovered a role for 70 kilodalton heat shock proteins (Hsp70s) in enabling the post-translational insertion of proteins into the endoplasmic reticulum and mitochondrial membranes.Deshaies, R.J., Koch, B.D., Werner-Washburne, M., Craig, E.A., and Schekman, R. (1988). A subfamily of stress proteins facilitates translocation of secretory and mitochondrial precursor polypeptides. Nature 332, 800-805 This was the first specific, genetically- and biochemically-validated function to be discovered for a member of the Hsp70 family of proteins.
SCF and cullin–RING ubiquitin ligases: As a postdoctoral fellow working with Dr. Marc Kirschner at the University of California, San Francisco, Deshaies discovered a biochemical function for the ubiquitin-conjugated enzyme CDC34, which he showed mediates conjugation of ubiquitin onto G1 cyclin proteins in yeast cells.Deshaies, R.J., Chau, V., and Kirschner, M.W. (1995). Ubiquitination of the G1 cyclin Cln2p by a Cdc34p-dependent pathway. EMBO J. 14, 303-312
Upon starting his laboratory at Caltech, Deshaies studied the function of Cdc34 and how it relates to progression through the cell division cycle. These studies led his laboratory to discover the SCF complex SCFCdc4,Feldman, R.M.R., Correll, C.C., Kaplan, K.B., and Deshaies, R.J. (1997). A Complex of Cdc4, Skp1, and Cdc53/Cullin Catalyzes Ubiquitination of the Phosphorylated CDK Inhibitor Sic1. Cell 91, 221-230 which is the progenitor of what is now known to be a large family of ~250 enzymes known as cullin–RING ubiquitin ligases (CRLs) that are conserved throughout eukaryotes and exert a major impact on the regulation of numerous cellular and organismal processes.Petroski, M.D. and Deshaies, R. J. (2005). Function and regulation of cullin-RING ubiquitin ligases. Nat. Rev. Mol. Cell. Biol. 6, 9-20Deshaies, R.J. and Joazeiro, C.A.P. (2009). RING domain E3 ubiquitin ligases. Annu. Rev. Biochem. 78, 399-434 In parallel, they established the paradigm of phosphorylation-dependent targeting of SCF substrates.Verma, R., Annan, R., Huddleston, M., Carr, S., Reynard, G., and Deshaies, R.J. (1997). Phosphorylation of Sic1p by G1 cyclin/Cdk is required for its degradation and entry into S phase. Science 278, 455-460 His lab went on to discover the critical catalytic subunit of SCFCdc4 (known as Rbx1/Roc1/Hrt1) and describe its mechanism of action.Seol, J.H., Feldman, R.M.R., Zachariae, W., Shevchenko, A., Correll, C.C., Lyapina, S., Chi, Y., Galova, M., Claypool, J., Sandmeyer, S., Nasmyth, K., Shevchenko, A., and Deshaies, R.J. (1999). Cdc53/cullin and the essential Hrt1 RING-H2 subunit of SCF define a ubiquitin ligase module that activates the E2 enzyme Cdc34. Genes Dev. 13, 1614-1626 Subsequent studies identified key aspects of CRL mechanism of action.Petroski, M.D. and Deshaies, R.J. (2005). Mechanism of lysine 48-linked ubiquitin-chain synthesis by the cullin-RING ubiquitin-ligase complex SCF-Cdc34. Cell 123, 1107-1120Pierce, N., Kleiger, G., Shan, S., and Deshaies, R.J. (2009). Detection of sequential ubiquitination on a millisecond time-scale. Nature 462, 615-619Kleiger, G., Saha, A., Lewis, S., Kuhlman, B., and Deshaies, R.J. (2009). Rapid E2-E3 assembly and disassembly enable processive ubiquitylation of cullin-RING ubiquitin ligase substrates. Cell 139, 957-968 Particularly notable were their discoveries relating to the CRL regulators COP9 signalosome (CSN) and CAND1. In 2001-2002, the Deshaies lab showed that CSN, together with proteasome subunit Rpn11/PSMD14, are the founding members of a novel family of deubiquitinating enzymes.Cope, G.A., Suh, G.S., Aravind, L., Schwarz, S.E., Zipursky, S.L., Koonin, E.V. and Deshaies, R.J. (2002). Role of predicted metalloprotease motif of Jab1/Csn5 in cleavage of NEDD8 from CUL1. Science 298, 608-611Verma, R., Aravind L., Oania, R., McDonald, W.H., Yates, J. R. III, Koonin, E.V. and Deshaies, R.J. (2002). Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S proteasome. Science 298, 611-615 CSN plays a key role in regulating SCF and other CRL enzymes by removing the ubiquitin-like protein NEDD8 from their cullin subunit.Lyapina, S., Cope, G., Shevchenko, A., Serino, G., Tsuge, T., Zhou, C., Wolf, D.A., Wei, N., Shevchenko, A., and Deshaies, R.J. (2001). Promotion of NEDD-CUL1 conjugate cleavage by COP9 signalsome. Science 18, 1382-1385 In 2013, they showed that Cand1 has the unusual property of being a ‘protein exchange catalyst’ that equilibrates F-box subunits of SCF ubiquitin ligases with the cullin scaffold subunit.Pierce, N.W., Lee, J.E., Liu, X., Sweredoski, M.J., Graham, R.L., Larimore, E.A., Rome, M., Zheng, N., Clurman, B.E., Hess, S., Shan, S.O., and Deshaies, R.J. (2013). Cand1 promotes assembly of new SCF complexes through dynamic exchange of F box proteins. Cell 153, 206-215
Proteasome: The Deshaies group pioneered the use of affinity purification to rapidly purify and characterize the composition of eukaryotic proteasomes, leading to the discovery of a large number of factors, including Rpn13 and Ubp6, that interact with the proteasome in yeast cells.Verma, R., Chen, S., Feldman, R., Schieltz, D., Yates, J., and Deshaies, R.J. (2000). Proteasomal proteomics: identification of nucleotide-sensitive proteasome-interacting proteins by mass spectrometric analysis of affinity-purified proteasomes. Mol. Biol. Cell 11, 3425-39 In subsequent work they discovered that the Rpn11 subunit mediates removal of polyubiquitin chains from proteasome substrates as they are being degraded.Verma, R., Aravind L., Oania, R., McDonald, W.H., Yates, J. R. III, Koonin, E.V. and Deshaies, R.J. (2002). Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S proteasome. Science 298, 611-615
P97/VCP: Early studies on p97 by the Deshaies group revealed a proteomic interaction network that includes all known UBX domain proteins, as well as a large number of ubiquitin ligase enzymes, including multiple CRLs.Alexandru, G., Graumann, J., Smith, G.T., Kolawa, N.J., Fang, R., and Deshaies, R.J. (2008). UBXD7 binds multiple ubiquitin ligases and implicates p97 in HIF1a turnover. Cell 134, 804-816 These findings indicated that the biological roles of p97 were far broader than was thought at the time. This was followed by identifying novel functions for p97, including removal of proteins from chromatin as part of the DNA damage response Verma, R., Oania, R., Fang, R., Smith, G.T., and Deshaies, R.J. (2011). Cdc48/p97 mediates UV-dependent turnover of RNA Pol II. Mol. Cell 41, 82-92 and extraction of stalled, nascent polypeptides from the ribosome.Verma, R., Oania, R.S., Kolawa, N.J., and Deshaies, R.J. (2013). Cdc48/p97 promotes degradation of aberrant nascent polypeptides bound to the ribosome. Elife 2, e00308