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Trigger factor both holds and folds its client proteins

Author

Listed:
  • Kevin Wu

    (University of Michigan)

  • Thomas C. Minshull

    (University of Leeds)

  • Sheena E. Radford

    (University of Leeds)

  • Antonio N. Calabrese

    (University of Leeds)

  • James C. A. Bardwell

    (University of Michigan)

Abstract

ATP-independent chaperones like trigger factor are generally assumed to play passive roles in protein folding by acting as holding chaperones. Here we show that trigger factor plays a more active role. Consistent with a role as an aggregation inhibiting chaperone, we find that trigger factor rapidly binds to partially folded glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and prevents it from non-productive self-association by shielding oligomeric interfaces. In the traditional view of holding chaperone action, trigger factor would then be expected to transfer its client to a chaperone foldase system for complete folding. Unexpectedly, we noticed that GAPDH folds into a monomeric but otherwise rather native-like intermediate state while trigger factor-bound. Upon release from trigger factor, the mostly folded monomeric GAPDH rapidly self-associates into its native tetramer and acquires enzymatic activity without needing additional folding factors. The mechanism we propose here for trigger factor bridges the holding and folding activities of chaperone function.

Suggested Citation

  • Kevin Wu & Thomas C. Minshull & Sheena E. Radford & Antonio N. Calabrese & James C. A. Bardwell, 2022. "Trigger factor both holds and folds its client proteins," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31767-6
    DOI: 10.1038/s41467-022-31767-6
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    References listed on IDEAS

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    1. Sophia Ungelenk & Fatemeh Moayed & Chi-Ting Ho & Tomas Grousl & Annette Scharf & Alireza Mashaghi & Sander Tans & Matthias P. Mayer & Axel Mogk & Bernd Bukau, 2016. "Small heat shock proteins sequester misfolding proteins in near-native conformation for cellular protection and efficient refolding," Nature Communications, Nature, vol. 7(1), pages 1-14, December.
    2. Rahmi Imamoglu & David Balchin & Manajit Hayer-Hartl & F. Ulrich Hartl, 2020. "Bacterial Hsp70 resolves misfolded states and accelerates productive folding of a multi-domain protein," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    3. Kevin Wu & Frederick Stull & Changhan Lee & James C. A. Bardwell, 2019. "Protein folding while chaperone bound is dependent on weak interactions," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    4. Rishav Mitra & Varun V. Gadkari & Ben A. Meinen & Carlo P. M. Mierlo & Brandon T. Ruotolo & James C. A. Bardwell, 2021. "Mechanism of the small ATP-independent chaperone Spy is substrate specific," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    5. Elke Deuerling & Agnes Schulze-Specking & Toshifumi Tomoyasu & Axel Mogk & Bernd Bukau, 1999. "Trigger factor and DnaK cooperate in folding of newly synthesized proteins," Nature, Nature, vol. 400(6745), pages 693-696, August.
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