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Bacterial Hsp70 resolves misfolded states and accelerates productive folding of a multi-domain protein

Author

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  • Rahmi Imamoglu

    (Max Planck Institute of Biochemistry, Department of Cellular Biochemistry)

  • David Balchin

    (Max Planck Institute of Biochemistry, Department of Cellular Biochemistry)

  • Manajit Hayer-Hartl

    (Max Planck Institute of Biochemistry, Department of Cellular Biochemistry)

  • F. Ulrich Hartl

    (Max Planck Institute of Biochemistry, Department of Cellular Biochemistry)

Abstract

The ATP-dependent Hsp70 chaperones (DnaK in E. coli) mediate protein folding in cooperation with J proteins and nucleotide exchange factors (E. coli DnaJ and GrpE, respectively). The Hsp70 system prevents protein aggregation and increases folding yields. Whether it also enhances the rate of folding remains unclear. Here we show that DnaK/DnaJ/GrpE accelerate the folding of the multi-domain protein firefly luciferase (FLuc) ~20-fold over the rate of spontaneous folding measured in the absence of aggregation. Analysis by single-pair FRET and hydrogen/deuterium exchange identified inter-domain misfolding as the cause of slow folding. DnaK binding expands the misfolded region and thereby resolves the kinetically-trapped intermediates, with folding occurring upon GrpE-mediated release. In each round of release DnaK commits a fraction of FLuc to fast folding, circumventing misfolding. We suggest that by resolving misfolding and accelerating productive folding, the bacterial Hsp70 system can maintain proteins in their native states under otherwise denaturing stress conditions.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14245-4
    DOI: 10.1038/s41467-019-14245-4
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    Cited by:

    1. Xiansha Xiao & Allison Fay & Pablo Santos Molina & Amanda Kovach & Michael S. Glickman & Huilin Li, 2024. "Structure of the M. tuberculosis DnaK−GrpE complex reveals how key DnaK roles are controlled," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Verena Rukes & Mathieu E. Rebeaud & Louis W. Perrin & Paolo De Los Rios & Chan Cao, 2024. "Single-molecule evidence of Entropic Pulling by Hsp70 chaperones," Nature Communications, Nature, vol. 15(1), pages 1-8, December.
    3. Matthias M. Schneider & Saurabh Gautam & Therese W. Herling & Ewa Andrzejewska & Georg Krainer & Alyssa M. Miller & Victoria A. Trinkaus & Quentin A. E. Peter & Francesco Simone Ruggeri & Michele Vend, 2021. "The Hsc70 disaggregation machinery removes monomer units directly from α-synuclein fibril ends," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    4. Ritaban Halder & Daniel A. Nissley & Ian Sitarik & Yang Jiang & Yiyun Rao & Quyen V. Vu & Mai Suan Li & Justin Pritchard & Edward P. O’Brien, 2023. "How soluble misfolded proteins bypass chaperones at the molecular level," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    5. 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.

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