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Development of NanoLuc-targeting protein degraders and a universal reporter system to benchmark tag-targeted degradation platforms

Author

Listed:
  • Christoph Grohmann

    (The Walter and Eliza Hall Institute for Medical Research
    University of Melbourne)

  • Charlene M. Magtoto

    (The Walter and Eliza Hall Institute for Medical Research
    University of Melbourne)

  • Joel R. Walker

    (Promega Biosciences LLC)

  • Ngee Kiat Chua

    (The Walter and Eliza Hall Institute for Medical Research
    University of Melbourne)

  • Anna Gabrielyan

    (The Walter and Eliza Hall Institute for Medical Research
    University of Melbourne)

  • Mary Hall

    (Promega Biosciences LLC)

  • Simon A. Cobbold

    (The Walter and Eliza Hall Institute for Medical Research)

  • Stephen Mieruszynski

    (The Walter and Eliza Hall Institute for Medical Research
    University of Melbourne)

  • Martin Brzozowski

    (The Walter and Eliza Hall Institute for Medical Research
    University of Melbourne)

  • Daniel S. Simpson

    (The Walter and Eliza Hall Institute for Medical Research
    University of Melbourne)

  • Hao Dong

    (The Walter and Eliza Hall Institute for Medical Research
    University of Melbourne)

  • Bridget Dorizzi

    (The Walter and Eliza Hall Institute for Medical Research
    University of Melbourne)

  • Annette V. Jacobsen

    (The Walter and Eliza Hall Institute for Medical Research
    University of Melbourne)

  • Emma Morrish

    (The Walter and Eliza Hall Institute for Medical Research
    University of Melbourne)

  • Natasha Silke

    (The Walter and Eliza Hall Institute for Medical Research
    University of Melbourne)

  • James M. Murphy

    (The Walter and Eliza Hall Institute for Medical Research
    University of Melbourne)

  • Joan K. Heath

    (The Walter and Eliza Hall Institute for Medical Research
    University of Melbourne)

  • Andrea Testa

    (Amphista Therapeutics Ltd)

  • Chiara Maniaci

    (Chemistry School of Natural and Environmental Sciences, Bedson Building, Newcastle University Edwards Walk)

  • Alessio Ciulli

    (School of Life Sciences, University of Dundee)

  • Guillaume Lessene

    (The Walter and Eliza Hall Institute for Medical Research
    University of Melbourne
    University of Melbourne)

  • John Silke

    (The Walter and Eliza Hall Institute for Medical Research
    University of Melbourne)

  • Rebecca Feltham

    (The Walter and Eliza Hall Institute for Medical Research
    University of Melbourne)

Abstract

Modulation of protein abundance using tag-Targeted Protein Degrader (tTPD) systems targeting FKBP12F36V (dTAGs) or HaloTag7 (HaloPROTACs) are powerful approaches for preclinical target validation. Interchanging tags and tag-targeting degraders is important to achieve efficient substrate degradation, yet limited degrader/tag pairs are available and side-by-side comparisons have not been performed. To expand the tTPD repertoire we developed catalytic NanoLuc-targeting PROTACs (NanoTACs) to hijack the CRL4CRBN complex and degrade NanoLuc tagged substrates, enabling rapid luminescence-based degradation screening. To benchmark NanoTACs against existing tTPD systems we use an interchangeable reporter system to comparatively test optimal degrader/tag pairs. Overall, we find the dTAG system exhibits superior degradation. To align tag-induced degradation with physiology we demonstrate that NanoTACs limit MLKL-driven necroptosis. In this work we extend the tTPD platform to include NanoTACs adding flexibility to tTPD studies, and benchmark each tTPD system to highlight the importance of comparing each system against each substrate.

Suggested Citation

  • Christoph Grohmann & Charlene M. Magtoto & Joel R. Walker & Ngee Kiat Chua & Anna Gabrielyan & Mary Hall & Simon A. Cobbold & Stephen Mieruszynski & Martin Brzozowski & Daniel S. Simpson & Hao Dong & , 2022. "Development of NanoLuc-targeting protein degraders and a universal reporter system to benchmark tag-targeted degradation platforms," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29670-1
    DOI: 10.1038/s41467-022-29670-1
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    References listed on IDEAS

    as
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