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Proteasome interaction with ubiquitinated substrates: from mechanisms to therapies

  1. Author:
    Chen,Xiang
    Htet, Zaw Min
    Lopez-Alfonzo, Erika
    Martin, Andreas
    Walters,Kylie
  2. Author Address

    NCI, Prot Proc Sect, Struct Biophys Lab, Ctr Canc Res, Frederick, MD 21701 USA.Univ Calif Berkeley, Dept Mol & Cell Biol, Calif Inst Quantitat Biosci, 229 Stanley Hall, Berkeley, CA 94720 USA.Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA.
    1. Year: 2020
    2. Date: DEC 11
    3. Epub Date: 2020 11 19
  1. Journal: The FEBS journal
  2. WILEY,
  3. Type of Article: Review
  4. ISSN: 1742-464X
  1. Abstract:

    The 26S proteasome is responsible for regulated proteolysis in eukaryotic cells. Its substrates are diverse in structure, function, sequence length, and amino acid composition, and are targeted to the proteasome by post-translational modification with ubiquitin. Ubiquitination occurs through a complex enzymatic cascade and can also signal for other cellular events, unrelated to proteasome-catalyzed degradation. Like other post-translational protein modifications, ubiquitination is reversible, with ubiquitin chain hydrolysis catalyzed by the action of deubiquitinating enzymes (DUBs), similar to 90 of which exist in humans and allow for temporal events and dynamic ubiquitin-chain remodeling. DUBs have been known for decades to be an integral part of the proteasome, as deubiquitination is coupled to substrate unfolding and translocation into the internal degradation chamber. Moreover, the proteasome also binds several ubiquitinating enzymes and shuttle factors that recruit ubiquitinated substrates. The role of this intricate machinery and how ubiquitinated substrates interact with proteasomes remains an area of active investigation. Here, we review what has been learned about the mechanisms used by the proteasome to bind ubiquitinated substrates, substrate shuttle factors, ubiquitination machinery, and DUBs. We also discuss many open questions that require further study or the development of innovative approaches to be answered. Finally, we address the promise of expanded therapeutic targeting that could benefit from such new discoveries.

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External Sources

  1. DOI: 10.1111/febs.15638
  2. PMID: 33211406
  3. WOS: 000597309100001

Library Notes

  1. Fiscal Year: FY2020-2021
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