# Dynamic modulation of p53 activity by its disordered regulatory domains

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2021 · $414,512

## Abstract

Approximately 30% of the proteins in the human proteome are intrinsically disordered (IDPs) or contain
long disordered regions (IDRs). IDPs play a central role in key cellular regulatory pathways and are
implicated in devastating diseases such as cancer, diabetes, cardiovascular disease, and
neurodegenerative disease. Disordered proteins are highly flexible and undergo transient and dynamic
intramolecular and intermolecular interactions that are central to their regulatory functions. Molecular
level characterization of the numerous human regulatory proteins that contain both structured and
disordered domains represents an enormous challenge to the traditional methods of structural biology.
Most studies to date have relied upon a reductionist approach, in which the ordered and disordered
regions are investigated in isolation. However, within the cell, the different domains of a given protein act
synergistically to allow it to perform its biological function and a full understanding of the underlying
molecular mechanism can only be achieved through a holistic, rather than reductionist, approach. The
overarching goal of this proposal is to utilize a non-reductionist approach to characterize the structural
ensemble and dynamics of the full-length tumor suppressor p53, which contains both globular and
disordered domains. An innovative, intein-based segmental isotope labeling strategy and advanced NMR
methods will be utilized to characterize the conformational ensemble and dynamics of full-length p53,
both free and in its complexes with specific and non-specific DNA targets. The disordered N- and C-
terminal regions of p53 regulate DNA binding through dynamic intramolecular and intermolecular
interactions that are modulated by constitutive and stress-induced posttranslational modifications. This
research will provide new molecular level insights into the mechanisms by which this important tumor
suppressor is dynamically regulated by the cascade of phosphorylation and acetylation that is triggered
by genotoxic stress.

## Key facts

- **NIH application ID:** 10124404
- **Project number:** 5R01GM075995-16
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** PETER Edwin WRIGHT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $414,512
- **Award type:** 5
- **Project period:** 2006-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10124404

## Citation

> US National Institutes of Health, RePORTER application 10124404, Dynamic modulation of p53 activity by its disordered regulatory domains (5R01GM075995-16). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10124404. Licensed CC0.

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