How soluble misfolded proteins bypass chaperones at the molecular level
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 a...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38962-z |
| _version_ | 1797795566798766080 |
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| author | Ritaban Halder Daniel A. Nissley Ian Sitarik Yang Jiang Yiyun Rao Quyen V. Vu Mai Suan Li Justin Pritchard Edward P. O’Brien |
| author_facet | Ritaban Halder Daniel A. Nissley Ian Sitarik Yang Jiang Yiyun Rao Quyen V. Vu Mai Suan Li Justin Pritchard Edward P. O’Brien |
| author_sort | Ritaban Halder |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T03:20:54Z |
| format | Article |
| id | doaj.art-28cea423dcfb4f54aedae0157fc7f68b |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T03:20:54Z |
| publishDate | 2023-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-28cea423dcfb4f54aedae0157fc7f68b2023-06-25T11:20:59ZengNature PortfolioNature Communications2041-17232023-06-0114111710.1038/s41467-023-38962-zHow soluble misfolded proteins bypass chaperones at the molecular levelRitaban Halder0Daniel A. Nissley1Ian Sitarik2Yang Jiang3Yiyun Rao4Quyen V. Vu5Mai Suan Li6Justin Pritchard7Edward P. O’Brien8Department of Chemistry, Pennsylvania State UniversityDepartment of Chemistry, Pennsylvania State UniversityDepartment of Chemistry, Pennsylvania State UniversityDepartment of Chemistry, Pennsylvania State UniversityMolecular, Cellular and Integrative Biosciences Program, The Huck Institutes of the Life Sciences, Pennsylvania State UniversityInstitute of Physics, Polish Academy of Sciences; Al. Lotnikow 32/46Institute of Physics, Polish Academy of Sciences; Al. Lotnikow 32/46Department of Biomedical Engineering, Pennsylvania State UniversityDepartment of Chemistry, Pennsylvania State UniversityAbstract 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.https://doi.org/10.1038/s41467-023-38962-z |
| spellingShingle | Ritaban Halder Daniel A. Nissley Ian Sitarik Yang Jiang Yiyun Rao Quyen V. Vu Mai Suan Li Justin Pritchard Edward P. O’Brien How soluble misfolded proteins bypass chaperones at the molecular level Nature Communications |
| title | How soluble misfolded proteins bypass chaperones at the molecular level |
| title_full | How soluble misfolded proteins bypass chaperones at the molecular level |
| title_fullStr | How soluble misfolded proteins bypass chaperones at the molecular level |
| title_full_unstemmed | How soluble misfolded proteins bypass chaperones at the molecular level |
| title_short | How soluble misfolded proteins bypass chaperones at the molecular level |
| title_sort | how soluble misfolded proteins bypass chaperones at the molecular level |
| url | https://doi.org/10.1038/s41467-023-38962-z |
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