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Cancer-Associated Mutations Perturb the Structure and Interactions of the Intrinsically Disordered p53 Transactivation Domain

Lynn G. Schrag, Indhujah Thevarajan, Xiaorong Liu, Om Prakash, Michal Zolkiewski, Jianhan Chen
doi: https://doi.org/10.1101/2020.12.12.422504
Lynn G. Schrag
1Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, KS 66505, USA
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Indhujah Thevarajan
1Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, KS 66505, USA
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Xiaorong Liu
2Department of Chemistry, University of Massachusetts Amherst, Amherst, MA 01003, USA
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Om Prakash
1Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, KS 66505, USA
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  • For correspondence: omp@ksu.edu michalz@ksu.edu jianhanc@umass.edu
Michal Zolkiewski
1Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, KS 66505, USA
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  • For correspondence: omp@ksu.edu michalz@ksu.edu jianhanc@umass.edu
Jianhan Chen
2Department of Chemistry, University of Massachusetts Amherst, Amherst, MA 01003, USA
3Department of Biochemistry and Molecular Biology, University of Massachusetts Amherst, Amherst, MA 01003, USA
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  • For correspondence: omp@ksu.edu michalz@ksu.edu jianhanc@umass.edu
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Abstract

Intrinsically disordered proteins (IDPs) are key components of regulatory networks that control crucial aspects of cell decision making. The intrinsically disordered transactivation domain (TAD) of tumor suppressor p53 mediates its interactions with multiple regulatory pathways to control the p53 homeostasis during the cellular response to genotoxic stress. Many cancer-associated mutations have been discovered in p53-TAD, but their structural and functional consequences are poorly understood. Here, by combining atomistic simulations, NMR spectroscopy, and binding assays, we demonstrate that cancer-associated mutations can significantly perturb the balance of p53 interactions with key activation and degradation regulators. Importantly, mutations do not all directly disrupt the known interaction interfaces. Instead, some mutations likely modulate the disordered state of p53-TAD, which affects the interactions. Our work suggests that the disordered conformational ensemble of p53-TAD can serve as a central conduit in regulating the response to various cellular stimuli at the protein-protein interaction level. Understanding how the disordered state of IDPs may be modulated by regulatory signals and/or disease associated perturbations will be essential in the studies on the role of IDPs in biology and diseases.

Competing Interest Statement

The authors have declared no competing interest.

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Posted December 12, 2020.
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Cancer-Associated Mutations Perturb the Structure and Interactions of the Intrinsically Disordered p53 Transactivation Domain
Lynn G. Schrag, Indhujah Thevarajan, Xiaorong Liu, Om Prakash, Michal Zolkiewski, Jianhan Chen
bioRxiv 2020.12.12.422504; doi: https://doi.org/10.1101/2020.12.12.422504
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Cancer-Associated Mutations Perturb the Structure and Interactions of the Intrinsically Disordered p53 Transactivation Domain
Lynn G. Schrag, Indhujah Thevarajan, Xiaorong Liu, Om Prakash, Michal Zolkiewski, Jianhan Chen
bioRxiv 2020.12.12.422504; doi: https://doi.org/10.1101/2020.12.12.422504

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