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Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis

Author

Listed:
  • Anna Plechanovová

    (Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK)

  • Ellis G. Jaffray

    (Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK)

  • Michael H. Tatham

    (Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK)

  • James H. Naismith

    (Biomedical Sciences Research Complex, University of St Andrews, St Andrews KY16 9ST, UK)

  • Ronald T. Hay

    (Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK)

Abstract

Ubiquitin modification is mediated by a large family of specificity determining ubiquitin E3 ligases. To facilitate ubiquitin transfer, RING E3 ligases bind both substrate and a ubiquitin E2 conjugating enzyme linked to ubiquitin via a thioester bond, but the mechanism of transfer has remained elusive. Here we report the crystal structure of the dimeric RING domain of rat RNF4 in complex with E2 (UbcH5A) linked by an isopeptide bond to ubiquitin. While the E2 contacts a single protomer of the RING, ubiquitin is folded back onto the E2 by contacts from both RING protomers. The carboxy-terminal tail of ubiquitin is locked into an active site groove on the E2 by an intricate network of interactions, resulting in changes at the E2 active site. This arrangement is primed for catalysis as it can deprotonate the incoming substrate lysine residue and stabilize the consequent tetrahedral transition-state intermediate.

Suggested Citation

  • Anna Plechanovová & Ellis G. Jaffray & Michael H. Tatham & James H. Naismith & Ronald T. Hay, 2012. "Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis," Nature, Nature, vol. 489(7414), pages 115-120, September.
    • Handle: RePEc:nat:nature:v:489:y:2012:i:7414:d:10.1038_nature11376
    DOI: 10.1038/nature11376
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    Citations

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    Cited by:

    1. Xiangyi S. Wang & Thomas R. Cotton & Sarah J. Trevelyan & Lachlan W. Richardson & Wei Ting Lee & John Silke & Bernhard C. Lechtenberg, 2023. "The unifying catalytic mechanism of the RING-between-RING E3 ubiquitin ligase family," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Shuhei Onishi & Kotone Uchiyama & Ko Sato & Chikako Okada & Shunsuke Kobayashi & Keisuke Hamada & Tomohiro Nishizawa & Osamu Nureki & Kazuhiro Ogata & Toru Sengoku, 2024. "Structure of the human Bre1 complex bound to the nucleosome," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    3. Andrej Paluda & Adam J. Middleton & Claudia Rossig & Peter D. Mace & Catherine L. Day, 2022. "Ubiquitin and a charged loop regulate the ubiquitin E3 ligase activity of Ark2C," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. Mohammad Afsar & GuanQun Liu & Lijia Jia & Eliza A. Ruben & Digant Nayak & Zuberwasim Sayyad & Priscila dos Santos Bury & Kristin E. Cano & Anindita Nayak & Xiang Ru Zhao & Ankita Shukla & Patrick Sun, 2023. "Cryo-EM structures of Uba7 reveal the molecular basis for ISG15 activation and E1-E2 thioester transfer," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. Diego Esposito & Jane Dudley-Fraser & Acely Garza-Garcia & Katrin Rittinger, 2022. "Divergent self-association properties of paralogous proteins TRIM2 and TRIM3 regulate their E3 ligase activity," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    6. Frank Herkules & Corey H. Yu & Alexander B. Taylor & Vi Dougherty & Susan T. Weintraub & Dmitri N. Ivanov, 2022. "Structural and functional asymmetry of RING trimerization controls priming and extension events in TRIM5α autoubiquitylation," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    7. J. Josephine Botsch & Roswitha Junker & Michèle Sorgenfrei & Patricia P. Ogger & Luca Stier & Susanne Gronau & Peter J. Murray & Markus A. Seeger & Brenda A. Schulman & Bastian Bräuning, 2024. "Doa10/MARCH6 architecture interconnects E3 ligase activity with lipid-binding transmembrane channel to regulate SQLE," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    8. Simon Maria Kienle & Tobias Schneider & Katrin Stuber & Christoph Globisch & Jasmin Jansen & Florian Stengel & Christine Peter & Andreas Marx & Michael Kovermann & Martin Scheffner, 2022. "Electrostatic and steric effects underlie acetylation-induced changes in ubiquitin structure and function," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    9. Nathalia Varejão & Jara Lascorz & Joan Codina-Fabra & Gemma Bellí & Helena Borràs-Gas & Jordi Torres-Rosell & David Reverter, 2021. "Structural basis for the E3 ligase activity enhancement of yeast Nse2 by SUMO-interacting motifs," Nature Communications, Nature, vol. 12(1), pages 1-14, December.

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