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Structural basis for substrate gripping and translocation by the ClpB AAA+ disaggregase

Author

Listed:
  • Alexandrea N. Rizo

    (University of Michigan
    University of California)

  • JiaBei Lin

    (Perelman School of Medicine at the University of Pennsylvania)

  • Stephanie N. Gates

    (University of Michigan)

  • Eric Tse

    (University of California)

  • Stephen M. Bart

    (Perelman School of Medicine at the University of Pennsylvania)

  • Laura M. Castellano

    (Perelman School of Medicine at the University of Pennsylvania)

  • Frank DiMaio

    (University of Washington)

  • James Shorter

    (Perelman School of Medicine at the University of Pennsylvania)

  • Daniel R. Southworth

    (University of California)

Abstract

Bacterial ClpB and yeast Hsp104 are homologous Hsp100 protein disaggregases that serve critical functions in proteostasis by solubilizing protein aggregates. Two AAA+ nucleotide binding domains (NBDs) power polypeptide translocation through a central channel comprised of a hexameric spiral of protomers that contact substrate via conserved pore-loop interactions. Here we report cryo-EM structures of a hyperactive ClpB variant bound to the model substrate, casein in the presence of slowly hydrolysable ATPγS, which reveal the translocation mechanism. Distinct substrate-gripping interactions are identified for NBD1 and NBD2 pore loops. A trimer of N-terminal domains define a channel entrance that binds the polypeptide substrate adjacent to the topmost NBD1 contact. NBD conformations at the seam interface reveal how ATP hydrolysis-driven substrate disengagement and re-binding are precisely tuned to drive a directional, stepwise translocation cycle.

Suggested Citation

  • Alexandrea N. Rizo & JiaBei Lin & Stephanie N. Gates & Eric Tse & Stephen M. Bart & Laura M. Castellano & Frank DiMaio & James Shorter & Daniel R. Southworth, 2019. "Structural basis for substrate gripping and translocation by the ClpB AAA+ disaggregase," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10150-y
    DOI: 10.1038/s41467-019-10150-y
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    Cited by:

    1. Chengying Ma & Damu Wu & Qian Chen & Ning Gao, 2022. "Structural dynamics of AAA + ATPase Drg1 and mechanism of benzo-diazaborine inhibition," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Harim I. Won & Samuel Zinga & Olga Kandror & Tatos Akopian & Ian D. Wolf & Jessica T. P. Schweber & Ernst W. Schmid & Michael C. Chao & Maya Waldor & Eric J. Rubin & Junhao Zhu, 2024. "Targeted protein degradation in mycobacteria uncovers antibacterial effects and potentiates antibiotic efficacy," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Claudio Mirabello & Björn Wallner & Björn Nystedt & Stavros Azinas & Marta Carroni, 2024. "Unmasking AlphaFold to integrate experiments and predictions in multimeric complexes," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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