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Seesaw conformations of Npl4 in the human p97 complex and the inhibitory mechanism of a disulfiram derivative.

<div class='caption-title'>Three conformational states of human p97 in complex with Npl4/Ufd1.</div>
<div class='caption-title'>Three conformational states of human p97 in complex with Npl4/Ufd1 and polyubiquitinated Ub-Eos.</div>
<div class='caption-title'>Copper released from the disulfiram derivative CuET under oxidative conditions inhibits the unfolding activity of p97.</div>
Pan M, Zheng Q, Yu Y, Ai H, Xie Y, Zeng X, Wang C, Liu L, Zhao M
OpenAccess logo Nat Commun 12 121 (2021)
Cited: 27 times
EuropePMC logo PMID: 33402676

Abstract

p97, also known as valosin-containing protein (VCP) or Cdc48, plays a central role in cellular protein homeostasis. Human p97 mutations are associated with several neurodegenerative diseases. Targeting p97 and its cofactors is a strategy for cancer drug development. Despite significant structural insights into the fungal homolog Cdc48, little is known about how human p97 interacts with its cofactors. Recently, the anti-alcohol abuse drug disulfiram was found to target cancer through Npl4, a cofactor of p97, but the molecular mechanism remains elusive. Here, using single-particle cryo-electron microscopy (cryo-EM), we uncovered three Npl4 conformational states in complex with human p97 before ATP hydrolysis. The motion of Npl4 results from its zinc finger motifs interacting with the N domain of p97, which is essential for the unfolding activity of p97. In vitro and cell-based assays showed that the disulfiram derivative bis-(diethyldithiocarbamate)-copper (CuET) can bypass the copper transporter system and inhibit the function of p97 in the cytoplasm by releasing cupric ions under oxidative conditions, which disrupt the zinc finger motifs of Npl4, locking the essential conformational switch of the complex.

Reviews - 7jy5 mentioned but not cited (1)

  1. Molecular Mechanisms Driving and Regulating the AAA+ ATPase VCP/p97, an Important Therapeutic Target for Treating Cancer, Neurological and Infectious Diseases. Valimehr S, Sethi A, Shukla M, Bhattacharyya S, Kazemi M, Rouiller I. Biomolecules 13 737 (2023)

Articles - 7jy5 mentioned but not cited (1)

  1. Conserved L464 in p97 D1-D2 linker is critical for p97 cofactor regulated ATPase activity. Zhang X, Gui L, Li S, Nandi P, Columbres RC, Wong DE, Moen DR, Lin HJ, Chiu PL, Chou TF. Biochem J 478 3185-3204 (2021)


Reviews citing this publication (8)

  1. Cuproptosis: mechanisms and links with cancers. Xie J, Yang Y, Gao Y, He J. Mol Cancer 22 46 (2023)
  2. Recent Advances in Repurposing Disulfiram and Disulfiram Derivatives as Copper-Dependent Anticancer Agents. Kannappan V, Ali M, Small B, Rajendran G, Elzhenni S, Taj H, Wang W, Dou QP. Front Mol Biosci 8 741316 (2021)
  3. The revival of dithiocarbamates: from pesticides to innovative medical treatments. Kaul L, Süss R, Zannettino A, Richter K. iScience 24 102092 (2021)
  4. Targeting of client proteins to the VCP/p97/Cdc48 unfolding machine. Meyer H, van den Boom J. Front Mol Biosci 10 1142989 (2023)
  5. The Cryo-EM Effect: Structural Biology of Neurodegenerative Disease Proteostasis Factors. Creekmore BC, Chang YW, Lee EB. J Neuropathol Exp Neurol 80 494-513 (2021)
  6. Intersection of Redox Chemistry and Ubiquitylation: Post-Translational Modifications Required for Maintaining Cellular Homeostasis and Neuroprotection. Kane EI, Waters KL, Spratt DE. Cells 10 2121 (2021)
  7. The Fate of Two Unstoppable Trains After Arriving Destination: Replisome Disassembly During DNA Replication Termination. Xia Y. Front Cell Dev Biol 9 658003 (2021)
  8. Valosin containing protein (VCP): initiator, modifier, and potential drug target for neurodegenerative diseases. Chu S, Xie X, Payan C, Stochaj U. Mol Neurodegener 18 52 (2023)

Articles citing this publication (17)

  1. The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin. Krastev DB, Li S, Sun Y, Wicks AJ, Hoslett G, Weekes D, Badder LM, Knight EG, Marlow R, Pardo MC, Yu L, Talele TT, Bartek J, Choudhary JS, Pommier Y, Pettitt SJ, Tutt ANJ, Ramadan K, Lord CJ. Nat Cell Biol 24 62-73 (2022)
  2. Mechanistic insight into substrate processing and allosteric inhibition of human p97. Pan M, Yu Y, Ai H, Zheng Q, Xie Y, Liu L, Zhao M. Nat Struct Mol Biol 28 614-625 (2021)
  3. K29-linked ubiquitin signaling regulates proteotoxic stress response and cell cycle. Yu Y, Zheng Q, Erramilli SK, Pan M, Park S, Xie Y, Li J, Fei J, Kossiakoff AA, Liu L, Zhao M. Nat Chem Biol 17 896-905 (2021)
  4. TIMELESS-TIPIN and UBXN-3 promote replisome disassembly during DNA replication termination in Caenorhabditis elegans. Xia Y, Fujisawa R, Deegan TD, Sonneville R, Labib KPM. EMBO J 40 e108053 (2021)
  5. Interactome screening of C9orf72 dipeptide repeats reveals VCP sequestration and functional impairment by polyGA. Božič J, Motaln H, Janež AP, Markič L, Tripathi P, Yamoah A, Aronica E, Lee YB, Heilig R, Fischer R, Thompson AJ, Goswami A, Rogelj B. Brain 145 684-699 (2022)
  6. Disulfiram ameliorates nonalcoholic steatohepatitis by modulating the gut microbiota and bile acid metabolism. Lei Y, Tang L, Chen Q, Wu L, He W, Tu D, Wang S, Chen Y, Liu S, Xie Z, Wei H, Yang S, Tang B. Nat Commun 13 6862 (2022)
  7. Multiple UBX proteins reduce the ubiquitin threshold of the mammalian p97-UFD1-NPL4 unfoldase. Fujisawa R, Polo Rivera C, Labib KPM. Elife 11 e76763 (2022)
  8. AAA+ ATPase p97/VCP mutants and inhibitor binding disrupt inter-domain coupling and subsequent allosteric activation. Caffrey B, Zhu X, Berezuk A, Tuttle K, Chittori S, Subramaniam S. J Biol Chem 297 101187 (2021)
  9. One-Step Synthesis of Nanoliposomal Copper Diethyldithiocarbamate and Its Assessment for Cancer Therapy. Paun RA, Dumut DC, Centorame A, Thuraisingam T, Hajduch M, Mistrik M, Dzubak P, De Sanctis JB, Radzioch D, Tabrizian M. Pharmaceutics 14 640 (2022)
  10. Integrating the Epigenome and Transcriptome of Hepatocellular Carcinoma to Identify Systematic Enhancer Aberrations and Establish an Aberrant Enhancer-Related Prognostic Signature. Huang P, Zhang B, Zhao J, Li MD. Front Cell Dev Biol 10 827657 (2022)
  11. A drug repurposing strategy for overcoming human multiple myeloma resistance to standard-of-care treatment. Chroma K, Skrott Z, Gursky J, Bacovsky J, Moudry P, Buchtova T, Mistrik M, Bartek J. Cell Death Dis 13 203 (2022)
  12. Cryo-EM structures of human p97 double hexamer capture potentiated ATPase-competent state. Gao H, Li F, Ji Z, Shi Z, Li Y, Yu H. Cell Discov 8 19 (2022)
  13. The p97-Nploc4 ATPase complex plays a role in muscle atrophy during cancer and amyotrophic lateral sclerosis. Re Cecconi AD, Barone M, Gaspari S, Tortarolo M, Bendotti C, Porcu L, Terribile G, Piccirillo R. J Cachexia Sarcopenia Muscle 13 2225-2241 (2022)
  14. A targeted covalent inhibitor of p97 with proteome-wide selectivity. Ye Z, Wang K, Chen L, Jin X, Chen H, Tang G, Yao SQ, Feng Z, Zhang CJ. Acta Pharm Sin B 12 982-989 (2022)
  15. SUMO enhances unfolding of SUMO-polyubiquitin-modified substrates by the Ufd1/Npl4/Cdc48 complex. Lee HG, Lemmon AA, Lima CD. Proc Natl Acad Sci U S A 120 e2213703120 (2023)
  16. Thicker Ice Improves the Integrity and Angular Distribution of CDC48A Hexamers on Cryo-EM Grids. Huntington B, Zhao L, Bron P, Shahul Hameed UF, Arold ST, Qureshi BM. Front Mol Biosci 9 890390 (2022)
  17. Inhibiting the compensatory elevation of xCT collaborates with disulfiram/copper-induced GSH consumption for cascade ferroptosis and cuproptosis. Zhang P, Zhou C, Ren X, Jing Q, Gao Y, Yang C, Shen Y, Zhou Y, Hu W, Jin F, Xu H, Yu L, Liu Y, Tong X, Li Y, Wang Y, Du J. Redox Biol 69 103007 (2024)


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