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Structural biases in disordered proteins are prevalent in the cell

View ORCID ProfileDavid Moses, View ORCID ProfileKarina Guadalupe, View ORCID ProfileFeng Yu, View ORCID ProfileEduardo Flores, Anthony Perez, Ralph McAnelly, View ORCID ProfileNora M. Shamoon, View ORCID ProfileEstefania Cuevas-Zepeda, View ORCID ProfileAndrea D. Merg, View ORCID ProfileErik W. Martin, View ORCID ProfileAlex S. Holehouse, View ORCID ProfileShahar Sukenik
doi: https://doi.org/10.1101/2021.11.24.469609
David Moses
1Department of Chemistry and Biochemistry, University of California, Merced, CA
2Center for Cellular and Biomolecular Machines, University of California, Merced, CA
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Karina Guadalupe
1Department of Chemistry and Biochemistry, University of California, Merced, CA
2Center for Cellular and Biomolecular Machines, University of California, Merced, CA
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Feng Yu
2Center for Cellular and Biomolecular Machines, University of California, Merced, CA
3Quantitative Systems Biology Program, University of California, Merced, CA
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Eduardo Flores
1Department of Chemistry and Biochemistry, University of California, Merced, CA
2Center for Cellular and Biomolecular Machines, University of California, Merced, CA
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Anthony Perez
1Department of Chemistry and Biochemistry, University of California, Merced, CA
2Center for Cellular and Biomolecular Machines, University of California, Merced, CA
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Ralph McAnelly
1Department of Chemistry and Biochemistry, University of California, Merced, CA
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Nora M. Shamoon
2Center for Cellular and Biomolecular Machines, University of California, Merced, CA
4California State University, Stanislaus, Turlock, CA
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Estefania Cuevas-Zepeda
1Department of Chemistry and Biochemistry, University of California, Merced, CA
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  • ORCID record for Estefania Cuevas-Zepeda
Andrea D. Merg
1Department of Chemistry and Biochemistry, University of California, Merced, CA
2Center for Cellular and Biomolecular Machines, University of California, Merced, CA
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Erik W. Martin
5Department of Structural Biology, St Jude Children’s Research Hospital, Memphis, TN
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Alex S. Holehouse
6Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO
7Center for Science and Engineering of Living Systems, Washington University in St. Louis, St. Louis, MO
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Shahar Sukenik
1Department of Chemistry and Biochemistry, University of California, Merced, CA
2Center for Cellular and Biomolecular Machines, University of California, Merced, CA
3Quantitative Systems Biology Program, University of California, Merced, CA
8Health Sciences Research Institute, University of California, Merced, CA
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  • For correspondence: ssukenik@ucmerced.edu
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Abstract

Intrinsically disordered proteins and protein regions (IDPs) are essential to cellular function in all proteomes. Unlike folded proteins, IDPs exist in an ensemble of rapidly interchanging conformations. IDP sequences encode interactions that create structural biases within the ensemble. Such structural biases determine the three-dimensional shape of IDP ensembles and can affect their activity. However, the plasticity and sensitivity of IDP ensembles means structural biases, often measured in vitro, may differ in the dynamic and heterogeneous intracellular environment. Here we reveal that structural biases found in vitro in well-studied IDPs persist inside human-derived cells. We further show that a subset of IDPs are able to sense changes in cellular physical-chemical composition and modulate their ensemble in response. We propose that IDP ensembles can evolve to sense and respond to intracellular physicochemical changes, or to resist them. This property can be leveraged for biological function, be the underlying cause of IDP-driven pathology, or be leveraged for the design of disorder-based biosensors and actuators.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Now showing in-cell data for 4 additional IDPs. The narrative has been changed to focus on the similarity of IDP ensembles in vitro and in cells. All new text and figures.

  • https://github.com/sukeniklab/IDP_structural_bias

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted May 12, 2022.
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Structural biases in disordered proteins are prevalent in the cell
David Moses, Karina Guadalupe, Feng Yu, Eduardo Flores, Anthony Perez, Ralph McAnelly, Nora M. Shamoon, Estefania Cuevas-Zepeda, Andrea D. Merg, Erik W. Martin, Alex S. Holehouse, Shahar Sukenik
bioRxiv 2021.11.24.469609; doi: https://doi.org/10.1101/2021.11.24.469609
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Structural biases in disordered proteins are prevalent in the cell
David Moses, Karina Guadalupe, Feng Yu, Eduardo Flores, Anthony Perez, Ralph McAnelly, Nora M. Shamoon, Estefania Cuevas-Zepeda, Andrea D. Merg, Erik W. Martin, Alex S. Holehouse, Shahar Sukenik
bioRxiv 2021.11.24.469609; doi: https://doi.org/10.1101/2021.11.24.469609

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