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Allosteric regulation of the 20S proteasome by the Catalytic Core Regulators (CCRs) family

Author

Listed:
  • Fanindra Kumar Deshmukh

    (Weizmann Institute of Science)

  • Gili Ben-Nissan

    (Weizmann Institute of Science)

  • Maya A. Olshina

    (Weizmann Institute of Science)

  • Maria G. Füzesi-Levi

    (Weizmann Institute of Science)

  • Caley Polkinghorn

    (Weizmann Institute of Science)

  • Galina Arkind

    (Weizmann Institute of Science)

  • Yegor Leushkin

    (Weizmann Institute of Science)

  • Irit Fainer

    (Weizmann Institute of Science)

  • Sarel J. Fleishman

    (Weizmann Institute of Science)

  • Dan Tawfik

    (Weizmann Institute of Science)

  • Michal Sharon

    (Weizmann Institute of Science)

Abstract

Controlled degradation of proteins is necessary for ensuring their abundance and sustaining a healthy and accurately functioning proteome. One of the degradation routes involves the uncapped 20S proteasome, which cleaves proteins with a partially unfolded region, including those that are damaged or contain intrinsically disordered regions. This degradation route is tightly controlled by a recently discovered family of proteins named Catalytic Core Regulators (CCRs). Here, we show that CCRs function through an allosteric mechanism, coupling the physical binding of the PSMB4 β-subunit with attenuation of the complex’s three proteolytic activities. In addition, by dissecting the structural properties that are required for CCR-like function, we could recapitulate this activity using a designed protein that is half the size of natural CCRs. These data uncover an allosteric path that does not involve the proteasome’s enzymatic subunits but rather propagates through the non-catalytic subunit PSMB4. This way of 20S proteasome-specific attenuation opens avenues for decoupling the 20S and 26S proteasome degradation pathways as well as for developing selective 20S proteasome inhibitors.

Suggested Citation

  • Fanindra Kumar Deshmukh & Gili Ben-Nissan & Maya A. Olshina & Maria G. Füzesi-Levi & Caley Polkinghorn & Galina Arkind & Yegor Leushkin & Irit Fainer & Sarel J. Fleishman & Dan Tawfik & Michal Sharon, 2023. "Allosteric regulation of the 20S proteasome by the Catalytic Core Regulators (CCRs) family," Nature Communications, Nature, vol. 14(1), pages 1-24, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38404-w
    DOI: 10.1038/s41467-023-38404-w
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    References listed on IDEAS

    as
    1. Remco Sprangers & Lewis E. Kay, 2007. "Quantitative dynamics and binding studies of the 20S proteasome by NMR," Nature, Nature, vol. 445(7128), pages 618-622, February.
    2. Oren Moscovitz & Gili Ben-Nissan & Irit Fainer & Dan Pollack & Limor Mizrachi & Michal Sharon, 2015. "The Parkinson’s-associated protein DJ-1 regulates the 20S proteasome," Nature Communications, Nature, vol. 6(1), pages 1-13, May.
    3. David Haselbach & Jil Schrader & Felix Lambrecht & Fabian Henneberg & Ashwin Chari & Holger Stark, 2017. "Long-range allosteric regulation of the human 26S proteasome by 20S proteasome-targeting cancer drugs," Nature Communications, Nature, vol. 8(1), pages 1-8, August.
    4. Indrajit Sahu & Sachitanand M. Mali & Prasad Sulkshane & Cong Xu & Andrey Rozenberg & Roni Morag & Manisha Priyadarsini Sahoo & Sumeet K. Singh & Zhanyu Ding & Yifan Wang & Sharleen Day & Yao Cong & O, 2021. "The 20S as a stand-alone proteasome in cells can degrade the ubiquitin tag," Nature Communications, Nature, vol. 12(1), pages 1-21, December.
    5. Ravit Netzer & Dina Listov & Rosalie Lipsh & Orly Dym & Shira Albeck & Orli Knop & Colin Kleanthous & Sarel J. Fleishman, 2018. "Ultrahigh specificity in a network of computationally designed protein-interaction pairs," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
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    Cited by:

    1. Wai Tuck Soh & Hanna P. Roetschke & John A. Cormican & Bei Fang Teo & Nyet Cheng Chiam & Monika Raabe & Ralf Pflanz & Fabian Henneberg & Stefan Becker & Ashwin Chari & Haiyan Liu & Henning Urlaub & Ju, 2024. "Protein degradation by human 20S proteasomes elucidates the interplay between peptide hydrolysis and splicing," Nature Communications, Nature, vol. 15(1), pages 1-25, December.

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