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. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. Devi S, Charvat A, Millbern Z, Vinueza N, Gestwicki JE. Exploration of the binding determinants of protein phosphatase 5 (PP5) reveals a chaperone-independent activation mechanism. J Biol Chem. 2024 Jul; 300(7):107435.  View on PubMed
  14. Yee SW, Ferrández-Peral L, Alentorn-Moron P, Fontsere C, Ceylan M, Koleske ML, Handin N, Artegoitia VM, Lara G, Chien HC, Zhou X, Dainat J, Zalevsky A, Sali A, Brand CM, Wolfreys FD, Yang J, Gestwicki JE, Capra JA, Artursson P, Newman JW, Marquès-Bonet T, Giacomini KM. Illuminating the function of the orphan transporter, SLC22A10, in humans and other primates. Nat Commun. 2024 May 23; 15(1):4380.  View on PubMed
  15. Wu T, Yu JC, Suresh A, Gale-Day ZJ, Alteen MG, Woo AS, Millbern Z, Johnson OT, Carroll EC, Partch CL, Fourches D, Vinueza NR, Vocadlo DJ, Gestwicki JE. Protein-adaptive differential scanning fluorimetry using conformationally responsive dyes. Nat Biotechnol. 2025 Jan; 43(1):106-113.  View on PubMed
  16. Lang BJ, Holton KM, Guerrero-Gimenez ME, Okusha Y, Magahis PT, Shi A, Neguse M, Venkatesh S, Nhu AM, Gestwicki JE, Calderwood SK. Heat shock protein 72 supports extracellular matrix production in metastatic mammary tumors. Cell Stress Chaperones. 2024 Jun; 29(3):456-471.  View on PubMed
  17. Liu C, Chen B, Xu P, Yang J, Nip C, Wang L, Shen Y, Ning S, Shang Y, Corey E, Gao AC, Gestwicki J, Wei Q, Liu L. Plexin D1 emerges as a novel target in the development of neural lineage plasticity in treatment-resistant prostate cancer. Res Sq. 2024 Mar 27.  View on PubMed
  18. Ahmad T, Alhammadi BA, Almaazmi SY, Arafa S, Blatch GL, Dutta T, Gestwicki JE, Keyzers RA, Shonhai A, Singh H. Plasmodium falciparum heat shock proteins as antimalarial drug targets: An update. Cell Stress Chaperones. 2024 Apr; 29(2):326-337.  View on PubMed
  19. Tanaka M, Fujikawa R, Sekiguchi T, Hernandez J, Johnson OT, Tanaka D, Kumafuji K, Serikawa T, Hoang Trung H, Hattori K, Mashimo T, Kuwamura M, Gestwicki JE, Kuramoto T. A missense mutation in the Hspa8 gene encoding heat shock cognate protein 70 causes neuroaxonal dystrophy in rats. Front Neurosci. 2024; 18:1263724.  View on PubMed
  20. Mayer MP, Blair L, Blatch GL, Borges TJ, Chadli A, Chiosis G, de Thonel A, Dinkova-Kostova A, Ecroyd H, Edkins AL, Eguchi T, Fleshner M, Foley KP, Fragkostefanakis S, Gestwicki J, Goloubinoff P, Heritz JA, Heske CM, Hibshman JD, Joutsen J, Li W, Lynes M, Mendillo ML, Mivechi N, Mokoena F, Okusha Y, Prahlad V, Repasky E, Sannino S, Scalia F, Shalgi R, Sistonen L, Sontag E, van Oosten-Hawle P, Vihervaara A, Wickramaratne A, Wang SXY, Zininga T. Stress biology: Complexity and multifariousness in health and disease. Cell Stress Chaperones. 2024 Feb; 29(1):143-157.  View on PubMed

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