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Universal protein misfolding intermediates can bypass the proteostasis network and remain soluble and less functional

Author

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  • Daniel A. Nissley

    (Pennsylvania State University)

  • Yang Jiang

    (Pennsylvania State University)

  • Fabio Trovato

    (Pennsylvania State University)

  • Ian Sitarik

    (Pennsylvania State University)

  • Karthik B. Narayan

    (Pennsylvania State University)

  • Philip To

    (Johns Hopkins University)

  • Yingzi Xia

    (Johns Hopkins University)

  • Stephen D. Fried

    (Johns Hopkins University
    Johns Hopkins University)

  • Edward P. O’Brien

    (Pennsylvania State University
    The Huck Institutes of the Life Sciences, Pennsylvania State University
    Institute for Computational and Data Sciences, Pennsylvania State University)

Abstract

Some misfolded protein conformations can bypass proteostasis machinery and remain soluble in vivo. This is an unexpected observation, as cellular quality control mechanisms should remove misfolded proteins. Three questions, then, are: how do long-lived, soluble, misfolded proteins bypass proteostasis? How widespread are such misfolded states? And how long do they persist? We address these questions using coarse-grain molecular dynamics simulations of the synthesis, termination, and post-translational dynamics of a representative set of cytosolic E. coli proteins. We predict that half of proteins exhibit misfolded subpopulations that bypass molecular chaperones, avoid aggregation, and will not be rapidly degraded, with some misfolded states persisting for months or longer. The surface properties of these misfolded states are native-like, suggesting they will remain soluble, while self-entanglements make them long-lived kinetic traps. In terms of function, we predict that one-third of proteins can misfold into soluble less-functional states. For the heavily entangled protein glycerol-3-phosphate dehydrogenase, limited-proteolysis mass spectrometry experiments interrogating misfolded conformations of the protein are consistent with the structural changes predicted by our simulations. These results therefore provide an explanation for how proteins can misfold into soluble conformations with reduced functionality that can bypass proteostasis, and indicate, unexpectedly, this may be a wide-spread phenomenon.

Suggested Citation

  • Daniel A. Nissley & Yang Jiang & Fabio Trovato & Ian Sitarik & Karthik B. Narayan & Philip To & Yingzi Xia & Stephen D. Fried & Edward P. O’Brien, 2022. "Universal protein misfolding intermediates can bypass the proteostasis network and remain soluble and less functional," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30548-5
    DOI: 10.1038/s41467-022-30548-5
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    1. Mian Zhou & Jinhu Guo & Joonseok Cha & Michael Chae & She Chen & Jose M. Barral & Matthew S. Sachs & Yi Liu, 2013. "Non-optimal codon usage affects expression, structure and function of clock protein FRQ," Nature, Nature, vol. 495(7439), pages 111-115, March.
    2. Susanna Röblitz & Marcus Weber, 2013. "Fuzzy spectral clustering by PCCA+: application to Markov state models and data classification," Advances in Data Analysis and Classification, Springer;German Classification Society - Gesellschaft für Klassifikation (GfKl);Japanese Classification Society (JCS);Classification and Data Analysis Group of the Italian Statistical Society (CLADAG);International Federation of Classification Societies (IFCS), vol. 7(2), pages 147-179, June.
    3. Shubhasis Haldar & Rafael Tapia-Rojo & Edward C. Eckels & Jessica Valle-Orero & Julio M. Fernandez, 2017. "Trigger factor chaperone acts as a mechanical foldase," Nature Communications, Nature, vol. 8(1), pages 1-7, December.
    4. Joost Van Durme & Sebastian Maurer-Stroh & Rodrigo Gallardo & Hannah Wilkinson & Frederic Rousseau & Joost Schymkowitz, 2009. "Accurate Prediction of DnaK-Peptide Binding via Homology Modelling and Experimental Data," PLOS Computational Biology, Public Library of Science, vol. 5(8), pages 1-9, August.
    5. Antonios C Tsolis & Nikos C Papandreou & Vassiliki A Iconomidou & Stavros J Hamodrakas, 2013. "A Consensus Method for the Prediction of ‘Aggregation-Prone’ Peptides in Globular Proteins," PLOS ONE, Public Library of Science, vol. 8(1), pages 1-6, January.
    6. Ulrich Schubert & Luis C. Antón & James Gibbs & Christopher C. Norbury & Jonathan W. Yewdell & Jack R. Bennink, 2000. "Rapid degradation of a large fraction of newly synthesized proteins by proteasomes," Nature, Nature, vol. 404(6779), pages 770-774, April.
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    Cited by:

    1. 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.

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