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Non-equilibrium dynamics of a nascent polypeptide during translation suppress its misfolding

Author

Listed:
  • Lisa M. Alexander

    (University of California Berkeley)

  • Daniel H. Goldman

    (University of California Berkeley
    Johns Hopkins University School of Medicine)

  • Liang M. Wee

    (University of California Berkeley
    Howard Hughes Medical Institute University of California Berkeley
    Lawrence Berkeley National Laboratory)

  • Carlos Bustamante

    (University of California Berkeley
    University of California Berkeley
    Howard Hughes Medical Institute University of California Berkeley
    Lawrence Berkeley National Laboratory)

Abstract

Protein folding can begin co-translationally. Due to the difference in timescale between folding and synthesis, co-translational folding is thought to occur at equilibrium for fast-folding domains. In this scenario, the folding kinetics of stalled ribosome-bound nascent chains should match the folding of nascent chains in real time. To test if this assumption is true, we compare the folding of a ribosome-bound, multi-domain calcium-binding protein stalled at different points in translation with the nascent chain as is it being synthesized in real-time, via optical tweezers. On stalled ribosomes, a misfolded state forms rapidly (1.5 s). However, during translation, this state is only attained after a long delay (63 s), indicating that, unexpectedly, the growing polypeptide is not equilibrated with its ensemble of accessible conformations. Slow equilibration on the ribosome can delay premature folding until adequate sequence is available and/or allow time for chaperone binding, thus promoting productive folding.

Suggested Citation

  • Lisa M. Alexander & Daniel H. Goldman & Liang M. Wee & Carlos Bustamante, 2019. "Non-equilibrium dynamics of a nascent polypeptide during translation suppress its misfolding," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10647-6
    DOI: 10.1038/s41467-019-10647-6
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    Cited by:

    1. Jose Ricardo Arias-Gonzalez, 2021. "Microscopically Reversible Pathways with Memory," Mathematics, MDPI, vol. 9(2), pages 1-21, January.
    2. Ferdinand Greiss & Nicolas Lardon & Leonie Schütz & Yoav Barak & Shirley S. Daube & Elmar Weinhold & Vincent Noireaux & Roy Bar-Ziv, 2024. "A genetic circuit on a single DNA molecule as an autonomous dissipative nanodevice," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    3. Naoto Soya & Haijin Xu & Ariel Roldan & Zhengrong Yang & Haoxin Ye & Fan Jiang & Aiswarya Premchandar & Guido Veit & Susan P. C. Cole & John Kappes & Tamás Hegedüs & Gergely L. Lukacs, 2023. "Folding correctors can restore CFTR posttranslational folding landscape by allosteric domain–domain coupling," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    4. Elena Plessa & Lien P. Chu & Sammy H. S. Chan & Oliver L. Thomas & Anaïs M. E. Cassaignau & Christopher A. Waudby & John Christodoulou & Lisa D. Cabrita, 2021. "Nascent chains can form co-translational folding intermediates that promote post-translational folding outcomes in a disease-causing protein," Nature Communications, Nature, vol. 12(1), pages 1-13, December.

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