Research Summary

The Gestwicki Laboratory is interested in molecular chaperones, protein homeostasis and protein misfolding disorders. To approach the big questions in this area, we use a chemical biology strategy that includes the discovery and optimization of new chemical inhibitors. We use these chemical probes to acutely perturb chaperone functions, revealing how these systems normally protect from cancer and neurodegeneration. Many of our chemical probes target allosteric and protein-protein interaction sites on the molecular chaperones and we have a significant interest in discovering inhibitors of "difficult" targets. We hope to better understand the logic of protein folding and misfolding and use this information to design more effective therapies.

Research Funding

  • September 30, 2021 - July 31, 2026 - Analysis of chemical modulators for corneal endothelial dystrophies , Co-Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01EY032161
  • August 5, 2021 - May 31, 2025 - Differential Scanning Fluorimetry (DSF) Methods for Studying Protein Stability , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01GM141299
  • September 1, 2020 - August 31, 2024 - Probing the Role of Chaperone-TPR Complexes in Tau Proteostasis , Principal Investigator . Sponsor: NIH, Sponsor Award ID: RF1AG068125
  • June 1, 2014 - February 28, 2019 - Exploration of Molecular Chaperone Complexes During Active Protein Triage , Co-Investigator . Sponsor: NIH, Sponsor Award ID: R01GM109896
  • August 15, 2016 - May 31, 2018 - Activation of the 20S Proteasome to Normalize Tau Homeostasis , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21AG053619
  • February 1, 2012 - January 31, 2014 - Natural Product-Inspired Method for Enhancing HIV Protease Inhibitors , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21AI098431
  • August 1, 2012 - March 31, 2013 - Chemical Probes and Chaperone-Accelerated Turnover of Tau , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21AG042813
  • February 1, 2008 - March 31, 2013 - Molecular Chaperones and Small Molecules , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01NS059690

Education

State University of New York - Fredonia, B.S., 1997, Chemistry
University of Wisconsin – Madison (with Laura L. Kiessling), PhD, 2002, Biochemistry
Stanford University (with Gerald R. Crabtree), 2005, Post-doctoral, Chemical Biology

Honors & Awards

  • 2020
    Everson Lecture, University of Wisconsin-Madison
  • 2019
    Chair, Bioorganic Chemistry GRC
  • 2018
    Elected Fellow, Cell Stress Society International (CSSI)
  • 2018
    Keynote Speaker, 9th International Symposium on Heat Shock Proteins in Biology and Medicine
  • 2018, 2019
    Dean's Apple Award, Outstanding Teaching in UCSF School of Pharmacy
  • 2017
    Director, Chemistry & Chemical Biology Ph.D. Program UCSF
  • 2015
    UCSF School of Pharmacy, Excellence in Teaching
  • 2014
    Named "Young Innovator" at UCSF
  • 2012
    Elected Fellow, American Association for the Advancement of Science (AAAS)
  • 2009
    National Science Foundation CAREER award

Selected Publications

  1. Moss T, Wooldredge A, Bhakta K, Cronin M, Gestwicki JE, Mukherjee S A conserved Hsp70 phosphorylation regulates cell cycle progression after DNA damage.  View on PubMed
  2. Torielli L, Castelli M, Milani F, Heritz JA, Cayaban SJ, Hernandez J, Serapian SA, Magni A, Frasnetti E, Doria F, Pirota V, Wengert LA, Woodford MR, Lodigiani G, Bergamaschi G, Veronesi M, Bandiera T, Girotto S, Paladino A, Prodromou C, Backe SJ, Bourboulia D, Canciani A, Arrigoni C, Lolicato M, Gestwicki JE, Mollapour M, Colombo G Design of multi-target peptide modulators for protein chaperone networks.  View on PubMed
  3. Carroll EC, Yang H, Powell WC, Charvat AF, Oehler A, Jones JG, Montgomery KM, Yung A, Millbern Z, Taylor AIP, Wilkinson M, Ranson NA, Radford SE, Vinueza NR, DeGrado WF, Mordes DA, Condello C, Gestwicki JE High-throughput discovery of fluoroprobes that recognize amyloid fibril polymorphs.  View on PubMed
  4. Charvat AF, Mason-Chalmers K, Grabinska-Rogala A, Shivakumar S, Gale-Day Z, Wu T, Millbern Z, Grimm JB, Carroll EC, Nilsson KPR, Lavis LD, Vinueza NR, Gestwicki JE Aurora 2.0: A fluorogenic dye library for expanding the capability of protein-adaptive differential scanning fluorimetry (paDSF).  View on PubMed
  5. Sang R, Gestwicki JE Radical Strategy to the Boron-to-Copper Transmetalation Problem: N-Alkylation with Alkylboronic Esters.  View on PubMed
  6. Bengoechea R, Findlay AR, Bhadra AK, Shao H, Stein KC, Pittman SK, Daw JA, Gestwicki JE, True HL, Weihl CC Inhibition of DNAJ-HSP70 interaction improves strength in muscular dystrophy.  View on PubMed
  7. Unnikrishnan A, Chung DH, Connelly EJ, Chuo SW, Devi S, Thwin AC, Nadel CM, Tse E, Gestwicki JE, Craik CS, Southworth DR Structures of Fab-stabilized CHIP reveal a conformational switch important in E3 ligase and chaperone functions.  View on PubMed
  8. Torielli L, Guarra F, Shao H, Gestwicki JE, Serapian SA, Colombo G Pathogenic mutation impairs functional dynamics of Hsp60 in mono- and oligomeric states.  View on PubMed
  9. Zhang JZ, Greenwood N, Hernandez J, Cuperus JT, Huang B, Ryder BD, Queitsch C, Gestwicki JE, Baker D. De novo designed Hsp70 activator dissolves intracellular condensates. Cell Chem Biol. 2025 Feb 04.  View on PubMed
  10. Chung DH, Connelly EJ, Unnikrishnan A, Chuo SW, Wucherer K, Nadel CM, Gestwicki JE, Southworth DR, Craik CS. Recombinant Antibodies Inhibit Enzymatic Activity of the E3 Ubiquitin Ligase CHIP via Multiple Mechanisms. J Biol Chem. 2025 Jan 23; 108220.  View on PubMed
  11. Pokhrel S, Devi S, Gestwicki JE. Chaperone-dependent and chaperone-independent functions of carboxylate clamp tetratricopeptide repeat (CC-TPR) proteins. Trends Biochem Sci. 2025 Feb; 50(2):121-133.  View on PubMed
  12. Samelson AJ, Ariqat N, McKetney J, Rohanitazangi G, Bravo CP, Bose R, Travaglini KJ, Lam VL, Goodness D, Dixon G, Marzette E, Jin J, Tian R, Tse E, Abskharon R, Pan H, Carroll EC, Lawrence RE, Gestwicki JE, Eisenberg D, Kanaan NM, Southworth DR, Gross JD, Gan L, Swaney DL, Kampmann M. CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis. bioRxiv. 2024 Nov 04.  View on PubMed
  13. Javed A, Johnson OT, Balana AT, Volk RF, Langen A, Ahn BS, Zaro BW, Gestwicki JE, Pratt MR. O-GlcNAc modification of HSP27 alters its protein interactions and promotes refolding of proteins through the BAG3/HSP70 co-chaperone. Protein Sci. 2024 Oct; 33(10):e5173.  View on PubMed
  14. Nadel CM, Pokhrel S, Wucherer K, Oehler A, Thwin AC, Basu K, Callahan MD, Southworth DR, Mordes DA, Craik CS, Gestwicki JE. Phosphorylation of tau at a single residue inhibits binding to the E3 ubiquitin ligase, CHIP. Nat Commun. 2024 Sep 12; 15(1):7972.  View on PubMed
  15. Carroll EC, Yang H, Jones JG, Oehler A, Charvat AF, Montgomery KM, Yung A, Millbern Z, Vinueza NR, DeGrado WF, Mordes DA, Condello C, Gestwicki JE. Methods for high throughput discovery of fluoroprobes that recognize tau fibril polymorphs. bioRxiv. 2024 Sep 02.  View on PubMed
  16. Xu P, Yang JC, Chen B, Ning S, Zhang X, Wang L, Nip C, Shen Y, Johnson OT, Grigorean G, Phinney B, Liu L, Wei Q, Corey E, Tepper CG, Chen HW, Evans CP, Dall'Era MA, Gao AC, Gestwicki JE, Liu C. Proteostasis perturbation of N-Myc leveraging HSP70 mediated protein turnover improves treatment of neuroendocrine prostate cancer. Nat Commun. 2024 Aug 05; 15(1):6626.  View on PubMed
  17. Theofilas P, Wang C, Butler D, Morales DO, Petersen C, Ambrose A, Chin B, Yang T, Khan S, Ng R, Kayed R, Karch CM, Miller BL, Gestwicki JE, Gan L, Temple S, Arkin MR, Grinberg LT. iPSC-induced neurons with the V337M MAPT mutation are selectively vulnerable to caspase-mediated cleavage of tau and apoptotic cell death. Mol Cell Neurosci. 2024 Sep; 130:103954.  View on PubMed
  18. Braxton JR, Shao H, Tse E, Gestwicki JE, Southworth DR. Asymmetric apical domain states of mitochondrial Hsp60 coordinate substrate engagement and chaperonin assembly. Nat Struct Mol Biol. 2024 Dec; 31(12):1848-1858.  View on PubMed
  19. Chen B, Xu P, Yang JC, Nip C, Wang L, Shen Y, Ning S, Shang Y, Corey E, Gao AC, Gestwicki JE, Wei Q, Liu L, Liu C. Plexin D1 emerges as a novel target in the development of neural lineage plasticity in treatment-resistant prostate cancer. Oncogene. 2024 Jul; 43(30):2325-2337.  View on PubMed
  20. Wu T, Gale-Day ZJ, Gestwicki JE. DSFworld: A flexible and precise tool to analyze differential scanning fluorimetry data. Protein Sci. 2024 Jun; 33(6):e5022.  View on PubMed

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