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Raymond J. Deshaies

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Raymond Joseph Deshaies (born September 25, 1961) is an American biochemist and cell biologist. He is senior vice president of global research at Amgen and a visiting associate at the California Institute of Technology (Caltech). 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.

Raymond J. Deshaies
Born (1961-09-25) September 25, 1961 (age 63)
Waterbury, Connecticut
NationalityAmerican
Alma materUniversity of California, Berkeley (PhD)
Cornell University (BS)
Known forDiscoveries of cullin–RING ubiquitin ligases and elucidation of their mechanism of action and regulation, the JAMM family of ubiquitin isopeptidases, PROTACs (heterobifunctional small molecules that promote target degradation) the Sec61 translocon, and nucleolar sequestration as a regulatory mechanism. Founder of Proteolix, which developed carfilzomib/Kyprolis®
Scientific career
FieldsBiochemistry, Cell Biology
InstitutionsAmgen
California Institute of Technology
Doctoral advisorRandy Schekman

Biography

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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. He performed postdoctoral studies at Berkeley (1988–1990) and subsequently at the University of California, San Francisco (1990–1994). He started as an assistant professor at Caltech in 1994 and was promoted to associate professor in 2000 and professor in 2005. In 2000, he was appointed as an assistant investigator of the Howard Hughes Medical Institute, and held the title of investigator from 2004–2017. He co-founded the biotechnology companies Proteolix and Cleave Biosciences in 2003 and 2011, respectively. He also founded the Proteome Exploration Laboratory at Caltech in 2006.

Scientific contributions

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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.[1][2] He went on to identify a complex of proteins that form the translocon in yeast cells.[3] 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.[4] 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.[5]

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,[6] 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.[7][8] In parallel, they established the paradigm of phosphorylation-dependent targeting of SCF substrates.[9] His lab went on to discover the critical catalytic subunit of SCFCdc4 (known as Rbx1/Roc1/Hrt1) and describe its mechanism of action.[10] Subsequent studies identified key aspects of CRL mechanism of action.[11][12][13] 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.[14][15] CSN plays a key role in regulating SCF and other CRL enzymes by removing the ubiquitin-like protein NEDD8 from their cullin subunit.[16] 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.[17]

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.[18] In subsequent work they discovered that the Rpn11 subunit mediates removal of polyubiquitin chains from proteasome substrates as they are being degraded.[19]

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.[20] 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 [21] and extraction of stalled, nascent polypeptides from the ribosome.[22]

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.[23] 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 [24] and removal of ubiquitin chains from substrates by Rpn11.[25] In addition, they discovered (in collaboration with Dr. Hugh Rosen of Scripps and Frank Schoenen of University of Kansas) the p97 inhibitors DBeQ [26] and ML240.[27] ML240 served as the basis for the development of CB-5083,[28] which entered human clinical trials in 2014.

Exit from mitosis: In addition to their studies on protein degradation, the Deshaies lab worked extensively on cell cycle control from 1994-2005, including studies on the regulation of exit from mitosis. They established the key paradigm that exit from mitosis is governed by the release of the protein phosphatase Cdc14 from its nucleolar anchor protein Net1 in late anaphase, which is triggered by the action of the mitotic exit network (MEN).[29] In later work, they established that an early step in the release of Cdc14 from Net1 is the phosphorylation of Net1 by the mitotic cyclin-Cdk complex [30]

Entrepreneurship

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In 2003, Deshaies co-founded Proteolix with Dr. Craig Crews (Yale), Dr. Susan Molineaux, and Dr. Phil Whitcome (deceased), based on technology developed in the Crews and Deshaies labs. Dr. Lawrence Lasky, of Latterell Venture Partners, also played an instrumental role. Proteolix built on technology invented by Dr. Crews to develop carfilzomib/Kyprolis® through mid-phase 2 clinical trials before being acquired by Onyx in 2009. Kyprolis® was approved by the FDA in 2012 for treatment of multiple myeloma, and in 2013 Amgen acquired Onyx.

In 2011, Deshaies co-founded Cleave Biosciences with Dr. Seth Cohen (University of California, San Diego), Dr. Frank Parlati, Dr. Peter Thompson, and Dr. Laura Shawver, based on technology developed in the Cohen and Deshaies labs. Dr. Lawrence Lasky, this time at US Venture Partners, once again played an instrumental role. Cleave built on technology invented collaboratively by the Deshaies, Rosen (Scripps), and Schoenen (University of Kansas) laboratories to develop CB-5083, which is a potent and selective inhibitor of p97. CB-5083 entered human phase 1 clinical trials in 2014.

In May 2017, Deshaies resigned from the California Institute of Technology and Howard Hughes Medical Institute to accept the position of Senior Vice President for discovery research at Amgen. In 2018 he was appointed SVP for global research and is in charge of all research projects up through filing of an IND application.

Awards

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References

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  1. ^ Deshaies, R.J., Fish, L.E., and Jagendorf, A.T. (1984). Permeability of chloroplast envelopes to Mg2+. Effects on protein synthesis. Plant Physiol. 74, 956-961
  2. ^ Stirling, 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
  3. ^ 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
  4. ^ 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
  5. ^ 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
  6. ^ 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
  7. ^ Petroski, M.D. and Deshaies, R. J. (2005). Function and regulation of cullin-RING ubiquitin ligases. Nat. Rev. Mol. Cell. Biol. 6, 9-20
  8. ^ Deshaies, R.J. and Joazeiro, C.A.P. (2009). RING domain E3 ubiquitin ligases. Annu. Rev. Biochem. 78, 399-434
  9. ^ 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
  10. ^ 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
  11. ^ 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, 1107-1120
  12. ^ Pierce, N., Kleiger, G., Shan, S., and Deshaies, R.J. (2009). Detection of sequential ubiquitination on a millisecond time-scale. Nature 462, 615-619
  13. ^ Kleiger, 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
  14. ^ 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, 608-611
  15. ^ 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
  16. ^ 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
  17. ^ 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
  18. ^ 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
  19. ^ 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
  20. ^ 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
  21. ^ 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
  22. ^ 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
  23. ^ 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
  24. ^ 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
  25. ^ Li, J; Yakushi, T; Parlati, F; Mackinnon, AL; Perez, C; Ma, Y; Carter, KP; Colayco, S; Magnuson, G; Brown, B; Nguyen, K; Vasile, S; Suyama, E; Smith, LH; Sergienko, E; Pinkerton, AB; Chung, TDY; Palmer, AE; Pass, I; Hess, S; Cohen, SM; Deshaies, RJ (2017). "Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11". Nature Chemical Biology. 13 (5): 486–493. doi:10.1038/nchembio.2326. PMC 5570473. PMID 28244987.
  26. ^ 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
  27. ^ 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
  28. ^ 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
  29. ^ Shou, W., Seol, J.H., Shevchenko, A., Baskerville, C., Moazed, D., Chen, Z.W.S., Jang, J., Shevchenko, A., Charbonneau, H., and Deshaies, R.J. (1999). Exit from mitosis triggered by Tem1-dependent release of the protein phosphatase Cdc14 from nucleolar RENT complex. Cell 97, 233-244
  30. ^ Azzam, R., Chen, S.L., Shou, W., Mah, A.S., Alexandru, G., Nasmyth, K., Annan, R.S., Carr, S.A., and Deshaies, R.J. (2004). Phosphorylation by cyclin B-Cdk underlies release of mitotic exit. Science 305, 516-519
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  • Kyprolis official website. [1]
  • Cleave Biosciences. [2]
  • Proteome Exploration Laboratory, Caltech. [3]
  • The Ubiquitin Proteome System. Lecture series by Raymond Deshaies, iBiology (video). [4]
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