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Detection of sequential polyubiquitylation on a millisecond timescale

Author

Listed:
  • Nathan W. Pierce

    (Howard Hughes Medical Institute, MC 156-29)

  • Gary Kleiger

    (Howard Hughes Medical Institute, MC 156-29)

  • Shu-ou Shan

    (MC 147-75, California Institute of Technology, 1200 East California Boulevard, Pasadena, California 91125, USA)

  • Raymond J. Deshaies

    (Howard Hughes Medical Institute, MC 156-29)

Abstract

The pathway by which ubiquitin chains are generated on substrate through a cascade of enzymes consisting of an E1, E2 and E3 remains unclear. Multiple distinct models involving chain assembly on E2 or substrate have been proposed. However, the speed and complexity of the reaction have precluded direct experimental tests to distinguish between potential pathways. Here we introduce new theoretical and experimental methodologies to address both limitations. A quantitative framework based on product distribution predicts that the really interesting new gene (RING) E3 enzymes SCFCdc4 and SCFβ-TrCP work with the E2 Cdc34 to build polyubiquitin chains on substrates by sequential transfers of single ubiquitins. Measurements with millisecond time resolution directly demonstrate that substrate polyubiquitylation proceeds sequentially. Our results present an unprecedented glimpse into the mechanism of RING ubiquitin ligases and illuminate the quantitative parameters that underlie the rate and pattern of ubiquitin chain assembly.

Suggested Citation

  • Nathan W. Pierce & Gary Kleiger & Shu-ou Shan & Raymond J. Deshaies, 2009. "Detection of sequential polyubiquitylation on a millisecond timescale," Nature, Nature, vol. 462(7273), pages 615-619, December.
    • Handle: RePEc:nat:nature:v:462:y:2009:i:7273:d:10.1038_nature08595
    DOI: 10.1038/nature08595
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    Cited by:

    1. Ryan P. Wurz & Huan Rui & Ken Dellamaggiore & Sudipa Ghimire-Rijal & Kaylee Choi & Kate Smither & Albert Amegadzie & Ning Chen & Xiaofen Li & Abhisek Banerjee & Qing Chen & Dane Mohl & Amit Vaish, 2023. "Affinity and cooperativity modulate ternary complex formation to drive targeted protein degradation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Fredrik Trulsson & Vyacheslav Akimov & Mihaela Robu & Nila Overbeek & David Aureliano Pérez Berrocal & Rashmi G. Shah & Jürgen Cox & Girish M. Shah & Blagoy Blagoev & Alfred C. O. Vertegaal, 2022. "Deubiquitinating enzymes and the proteasome regulate preferential sets of ubiquitin substrates," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Lida Xu & Zhilin Qu, 2012. "Roles of Protein Ubiquitination and Degradation Kinetics in Biological Oscillations," PLOS ONE, Public Library of Science, vol. 7(4), pages 1-11, April.
    4. Rui Li & Jingchen Shao & Young-June Jin & Haruya Kawase & Yu Ting Ong & Kerstin Troidl & Qi Quan & Lei Wang & Remy Bonnavion & Astrid Wietelmann & Francoise Helmbacher & Michael Potente & Johannes Gra, 2023. "Endothelial FAT1 inhibits angiogenesis by controlling YAP/TAZ protein degradation via E3 ligase MIB2," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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