Research Summary

I have spent 33 years doing research in therapeutic sciences and biotechnology development, first 16 years at Genentech and then 8 years at Sunesis (a company I founded) prior to joining UCSF 9 years ago. At Genentech, my group was among the first to develop gain-of-function engineering of enzymes and proteins by site-directed mutagenesis and phage display. At Sunesis, we developed novel technologies for fragment-based drug discovery, notably the site-directed approach Tethering. My lab at UCSF has developed the N-terminomics technology to characterize the caspase products cleaved during apoptosis. We currently have what we believe is the largest database of proteins that are cleaved by caspases (~2,000 targets in all), as well as targets cleaved in specific cells and their precise cleavage sites identified. More recently, we have extended our proteomics work to serum using the subtiligase tagging technology. This has allowed us to dive to very low abundance proteins in serum. We have also engineered a new small molecule activated protease, called the SNIPer. We have built a catalytic tagging device called the NEDDylator to interrogate molecular binding partners in cellular pathways involving E3 ligases. Recently, we have developed a motif-specific scaffold strategy for producing synthetic monoclonal antibodies specific to post-translational modifications. I am also Director of the Small Molecule Discovery Center (SMDC) at UCSF, a core facility that offers UCSF researchers access to modern small molecule discovery technologies including high-throughput screening, fragment-based drug discovery, and hit-to-lead medicinal chemistry. We have also built the Antibiome Center for generation of renewable recombinant antibodies to the proteome.

Research Funding

  • September 24, 2014 - August 31, 2019 - Antibody Research Technology Center , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P41CA196276
  • June 16, 2014 - May 31, 2019 - Affinity-directed tagging of protein binding partners in signaling , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01CA191018
  • April 1, 2007 - July 31, 2016 - Global Analysis of Proteolysis in Apoptosis , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01GM081051
  • March 1, 2014 - February 29, 2016 - Generation of recombinant thiopeptides to target antimicrobial-resistant bacteria , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21AI111662


University of California, Berkeley, CA, B.A., 1973, Biochemistry
Washington State University, Ph.D., 1979, Biochemistry
Washington State University, Postdoc, 1979-1980, Chemistry
Stanford University Medical School, Postdoc, 1980-1982, Biochemistry

Honors & Awards

  • 1979-1981
    Damon M. Runyon - Walter Winchell Postdoctoral Fellowship
  • 1990
    Pfizer Award (given by the American Chemical Society for achievements in enzyme chemistry)
  • 1998
    Recipient of the Christian B. Anfinsin Award presented by the Protein Society
  • 1998
    Recipient of the Vincent du Vignead Award given by the American Peptide Society
  • 1999
    Elected Member to the National Academy of Sciences
  • 2003
    Recipient of the Hans Neurath Award given by the Protein Society
  • 2006
    Perlman Lecture Award of the ACS biotechnology Division
  • 2017
    Named to first cohort of Chan Zuckerberg Biohub Investigators

Selected Publications

  1. Bartholow TG, Burroughs P, Elledge SK, Byrnes JR, Kirkemo LL, Garda V, Leung KK, Wells JA. Site-specific proximity labeling at single residue resolution for identification of protein partners in vitro and on cells. bioRxiv. 2023 Jul 27.  View on PubMed
  2. Solomon PE, Bracken CJ, Carozza JA, Wang H, Young EP, Wellner A, Liu CC, Sweet-Cordero EA, Li L, Wells JA. Discovery of VH domains that allosterically inhibit ENPP1. Nat Chem Biol. 2023 Jul 03.  View on PubMed
  3. Rettko NJ, Kirkemo LL, Wells JA. Secreted HLA Fc-Fusion Profiles Immunopeptidome in Hypoxic PDAC and Cellular Senescence. bioRxiv. 2023 Apr 12.  View on PubMed
  4. Chopra S, Trepka K, Sakhamuri S, Carretero-González A, Zhu J, Egusa E, Zhou J, Leung K, Zhao N, Hooshdaran N, Feng FY, Wells JA, Chou J, Evans MJ. Theranostic Targeting of CUB Domain-Containing Protein 1 (CDCP1) in Multiple Subtypes of Bladder Cancer. Clin Cancer Res. 2023 04 03; 29(7):1232-1242.  View on PubMed
  5. Remesh SG, Merz GE, Brilot AF, Chio US, Rizo AN, Pospiech TH, Lui I, Laurie MT, Glasgow J, Le CQ, Zhang Y, Diwanji D, Hernandez E, Lopez J, Mehmood H, Pawar KI, Pourmal S, Smith AM, Zhou F, QCRG Structural Biology Consortium, DeRisi J, Kortemme T, Rosenberg OS, Glasgow A, Leung KK, Wells JA, Verba KA. Computational pipeline provides mechanistic understanding of Omicron variant of concern neutralizing engineered ACE2 receptor traps. Structure. 2023 03 02; 31(3):253-264.e6.  View on PubMed
  6. Stopfer LE, Rettko NJ, Leddy O, Mesfin JM, Brown E, Winski S, Bryson B, Wells JA, White FM. MEK inhibition enhances presentation of targetable MHC-I tumor antigens in mutant melanomas. Proc Natl Acad Sci U S A. 2022 12 06; 119(49):e2208900119.  View on PubMed
  7. Schaefer K, Lui I, Byrnes JR, Kang E, Zhou J, Weeks AM, Wells JA. Direct Identification of Proteolytic Cleavages on Living Cells Using a Glycan-Tethered Peptide Ligase. ACS Cent Sci. 2022 Oct 26; 8(10):1447-1456.  View on PubMed
  8. Elledge SK, Eigl I, Phelps M, McClinton K, Zhou XX, Leung KK, Tato CM, Wells JA. Using Split Luminescent Biosensors for SARS-CoV-2 Antibody Detection in Serum, Plasma, and Blood Samples. Curr Protoc. 2022 Oct; 2(10):e521.  View on PubMed
  9. Pance K, Gramespacher JA, Byrnes JR, Salangsang F, Serrano JC, Cotton AD, Steri V, Wells JA. Modular cytokine receptor-targeting chimeras for targeted degradation of cell surface and extracellular proteins. Nat Biotechnol. 2023 02; 41(2):273-281.  View on PubMed
  10. Remesh SG, Merz GE, Brilot AF, Chio US, Rizo AN, Pospiech TH, Lui I, Laurie MT, Glasgow J, Le CQ, Zhang Y, Diwanji D, Hernandez E, Lopez J, Pawar KI, Pourmal S, Smith AM, Zhou F, QCRG Structural Biology Consortium, DeRisi J, Kortemme T, Rosenberg OS, Glasgow A, Leung KK, Wells JA, Verba KA. Computational pipeline provides mechanistic understanding of Omicron variant of concern neutralizing engineered ACE2 receptor traps. bioRxiv. 2022 Aug 10.  View on PubMed
  11. Zhao N, Chopra S, Trepka K, Wang YH, Sakhamuri S, Hooshdaran N, Kim H, Zhou J, Lim SA, Leung KK, Egusa EA, Zhu J, Zhang L, Foye A, Sriram R, Chan E, Seo Y, Feng FY, Small EJ, Chou J, Wells JA, Aggarwal R, Evans MJ. CUB Domain-Containing Protein 1 (CDCP1) Is a Target for Radioligand Therapy in Castration-Resistant Prostate Cancer, including PSMA Null Disease. Clin Cancer Res. 2022 07 15; 28(14):3066-3075.  View on PubMed
  12. Ferguson ID, Patiño-Escobar B, Tuomivaara ST, Lin YT, Nix MA, Leung KK, Kasap C, Ramos E, Nieves Vasquez W, Talbot A, Hale M, Naik A, Kishishita A, Choudhry P, Lopez-Girona A, Miao W, Wong SW, Wolf JL, Martin TG, Shah N, Vandenberg S, Prakash S, Besse L, Driessen C, Posey AD, Mullins RD, Eyquem J, Wells JA, Wiita AP. The surfaceome of multiple myeloma cells suggests potential immunotherapeutic strategies and protein markers of drug resistance. Nat Commun. 2022 07 15; 13(1):4121.  View on PubMed
  13. Jiang Z, Kuo YH, Zhong M, Zhang J, Zhou XX, Xing L, Wells JA, Wang Y, Arkin MR. Adaptor-Specific Antibody Fragment Inhibitors for the Intracellular Modulation of p97 (VCP) Protein-Protein Interactions. J Am Chem Soc. 2022 07 27; 144(29):13218-13225.  View on PubMed
  14. Li Z, Ferguson L, Deol KK, Roberts MA, Magtanong L, Hendricks JM, Mousa GA, Kilinc S, Schaefer K, Wells JA, Bassik MC, Goga A, Dixon SJ, Ingolia NT, Olzmann JA. Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability. Nat Chem Biol. 2022 07; 18(7):751-761.  View on PubMed
  15. Solomon PE, Kirkemo LL, Wilson GM, Leung KK, Almond MH, Sayles LC, Sweet-Cordero EA, Rosenberg OS, Coon JJ, Wells JA. Discovery Proteomics Analysis Determines That Driver Oncogenes Suppress Antiviral Defense Pathways Through Reduction in Interferon-β Autocrine Stimulation. Mol Cell Proteomics. 2022 07; 21(7):100247.  View on PubMed
  16. Gramespacher JA, Cotton AD, Burroughs PWW, Seiple IB, Wells JA. Roadmap for Optimizing and Broadening Antibody-Based PROTACs for Degradation of Cell Surface Proteins. ACS Chem Biol. 2022 05 20; 17(5):1259-1268.  View on PubMed
  17. Kirkemo LL, Elledge SK, Yang J, Byrnes JR, Glasgow JE, Blelloch R, Wells JA. Cell-surface tethered promiscuous biotinylators enable comparative small-scale surface proteomic analysis of human extracellular vesicles and cells. Elife. 2022 03 08; 11.  View on PubMed
  18. Martinko AJ, Simonds EF, Prasad S, Ponce A, Bracken CJ, Wei J, Wang YH, Chow TL, Huang Z, Evans MJ, Wells JA, Hill ZB. Switchable assembly and function of antibody complexes in vivo using a small molecule. Proc Natl Acad Sci U S A. 2022 03 01; 119(9).  View on PubMed
  19. Rettko NJ, Campisi J, Wells JA. Engineering Antibodies Targeting p16 MHC-Peptide Complexes. ACS Chem Biol. 2022 03 18; 17(3):545-555.  View on PubMed
  20. Byrnes JR, Weeks AM, Shifrut E, Carnevale J, Kirkemo L, Ashworth A, Marson A, Wells JA. Hypoxia Is a Dominant Remodeler of the Effector T Cell Surface Proteome Relative to Activation and Regulatory T Cell Suppression. Mol Cell Proteomics. 2022 04; 21(4):100217.  View on PubMed

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