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How soluble misfolded proteins bypass chaperones at the molecular level

Author

Listed:
  • Ritaban Halder

    (Pennsylvania State University)

  • Daniel A. Nissley

    (Pennsylvania State University
    University of Oxford)

  • Ian Sitarik

    (Pennsylvania State University)

  • Yang Jiang

    (Pennsylvania State University)

  • Yiyun Rao

    (Pennsylvania State University)

  • Quyen V. Vu

    (Polish Academy of Sciences; Al. Lotnikow 32/46)

  • Mai Suan Li

    (Polish Academy of Sciences; Al. Lotnikow 32/46
    Tan Chanh Hiep Ward)

  • Justin Pritchard

    (Pennsylvania State University
    Pennsylvania State University)

  • Edward P. O’Brien

    (Pennsylvania State University
    Pennsylvania State University
    Pennsylvania State University)

Abstract

Subpopulations of soluble, misfolded proteins can bypass chaperones within cells. The extent of this phenomenon and how it happens at the molecular level are unknown. Through a meta-analysis of the experimental literature we find that in all quantitative protein refolding studies there is always a subpopulation of soluble but misfolded protein that does not fold in the presence of one or more chaperones, and can take days or longer to do so. Thus, some misfolded subpopulations commonly bypass chaperones. Using multi-scale simulation models we observe that the misfolded structures that bypass various chaperones can do so because their structures are highly native like, leading to a situation where chaperones do not distinguish between the folded and near-native-misfolded states. More broadly, these results provide a mechanism by which long-time scale changes in protein structure and function can persist in cells because some misfolded states can bypass components of the proteostasis machinery.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38962-z
    DOI: 10.1038/s41467-023-38962-z
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    References listed on IDEAS

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