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Mapping Interactions of the Intrinsically Disordered C-Terminal Regions of Tetrameric p53 by Segmental Isotope Labeling and NMR
Open accessAbstract
The C-terminal region of the tumor suppressor protein p53 contains three domains, nuclear localization signal (NLS), tetramerization domain (TET), and C-terminal regulatory domain (CTD), which are essential for p53 function. Characterization of the structure and interactions of these domains within full-length p53 has been limited by the overall size and flexibility of the p53 tetramer. Using trans -intein splicing, we have generated full-length p53 constructs in which the C-terminal region is isotopically labeled with 15 N for NMR analysis, allowing us to obtain atomic-level information on the C-terminal domains in the context of the full-length protein. Resonances of NLS and CTD residues have narrow linewidths, showing that these regions are largely solvent-exposed and dynamically disordered, whereas resonances from the folded TET are broadened beyond detection. Two regions of the CTD, spanning residues 369–374 and 381–388 and with high lysine content, make dynamic and sequence-independent interactions with DNA in regions that flank the p53 recognition element. The population of DNA-bound states increases as the length of the flanking regions is extended up to approximately 20 base pairs on either side of the recognition element. Acetylation of K372, K373, and K382, using a construct of the transcriptional coactivator CBP containing the TAZ2 and acetyltransferase domains, inhibits interaction of the CTD with DNA. This work provides high-resolution insights into the behavior of the intrinsically disordered C-terminal regions of p53 within the full-length tetramer and the molecular basis by which the CTD mediates DNA binding and specificity.
Overview
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TL;DR
Using trans-intein splicing and segmental ¹⁵N labeling, the authors obtained atomic-level NMR data on the disordered C-terminal regions of full-length tetrameric p53. They show that the CTD dynamically binds DNA flanking the p53 recognition element, and that acetylation of K372/K373/K382 impairs this interaction.
Key findings
- The NLS and CTD remain largely disordered and highly dynamic in full-length p53; TET-domain resonances (Y327–G356) are broadened beyond detection in the full-length tetramer but are visible in the isolated p53(304–393) peptide.
- The CTD contacts DNA outside the 20-bp p53 recognition element: residues 369–374 and 381–388 show substantial chemical shift changes with a 60-bp DNA (DNA-L) but only minor changes with the 20-bp DNA-S. These interactions increase as flanking DNA length increases and level off beyond ~20 bp (~70 Å) on either side of the recognition element.
- CTD–DNA binding is sequence independent: similar CTD chemical shift changes occur with ATG-repeat flanks, random flanks, and native p21 flanks.
- Acetylation by CBP(1079–1855) at K372, K373, and K382 (confirmed by Western blot) impairs but does not completely abrogate CTD binding to DNA; K305 also showed chemical shift changes suggesting acetylation.
Methods
- Full-length p53 constructs contained the quadruple M133L/V203A/N239Y/N268D superstabilizing mutations; segmental labeling used Npu DnaE trans-intein splicing to produce p53 labeled with ¹⁵N at residues 304–393 [¹⁵N(304–393)-p53].
- NMR experiments included ¹H-¹⁵N HSQC, TROSY-HSQC, and SOFAST-HMQC at 25°C in 20 mM Tris, pH 7.0, 150 mM NaCl, 2 mM DTT, 5% D₂O; protein concentrations ranged from 30–150 μM. Backbone assignments for p53(304–393) were deposited in the BMRB under accession 51613.
- DNA constructs ranged from 20–80 bp, with a central 20-bp p53 recognition element flanked by 0–30 bp of (ATG)n or other sequences; p53:DNA complexes used a 4:1 protomer:DNA ratio (1:1 tetramer:DNA). Acetylation used CBP(1079–1855) at a 100:1 p53:CBP molar ratio with 1 mM acetyl-CoA.
Limitations
- The paper states that TET-domain backbone amide resonances are broadened beyond detection in full-length p53, so the authors cannot comment on potential TET:DNA interactions.
- The paper notes that four non-native residues (CFNG) are inserted at the splice site between S303/T304, causing substantial chemical shift differences for residues adjacent to the splice site.
- Evident from the text: all structural and interaction data are from in vitro purified-protein NMR experiments under defined buffer conditions, so the cellular context and physiological consequences of the observed CTD–DNA and acetylation effects are not directly measured.
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In the paper
“The population of DNA-bound states increases as the length of the flanking regions is extended up to approximately 20 base pairs on either side of the recognition element.”
- Also stated in: § Binding of the CTD to DNA is enhanced by increasing DNA length · plain
“As the length of the flanking regions increases, the chemical shift perturbations of CTD resonances relative to the unbound p53 tetramer increase proportionally (Figure 4C), but level off beyond ~20 flanking base-pairs (in the 60 and 80 base-pair oligonucleotides) (Figure 4C).”
§ Mapping Interactions of the Intrinsically Disordered C-Terminal Regions of Tetrameric p53 by Segmental Isotope Labeling and NMR > Abstract
plainstates a cause- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption not shown here.
- Also stated in: § Binding of the CTD to DNA is enhanced by increasing DNA length · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“resonances from the folded tetramerization domain are broadened beyond detection”
- Also stated in: § The NLS and CTD are disordered in full-length p53 · plain
“The cross-peaks for residues 326 to 356, corresponding to the TET domain, 14,51-54 are unobservable in the HSQC spectrum of the segmentally labeled p53 tetramer but are visible and well dispersed in the spectrum of the p53(304-393) peptide (Figure 2B).”
§ Mapping Interactions of the Intrinsically Disordered C-Terminal Regions of Tetrameric p53 by Segmental Isotope Labeling and NMR > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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- Rests on an assumption not shown here.
- Also stated in: § The NLS and CTD are disordered in full-length p53 · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Two regions of the CTD, spanning residues 369-374 and 381-388 and with high lysine content, make dynamic and sequence-independent interactions with DNA in regions that flank the p53 recognition element.”
- Also stated in: § The CTD contacts DNA outside the p53 recognition element · hedged
“binding to the longer DNA-L oligonucleotide results in substantial chemical shift changes for cross peaks associated with residues 369-374 and 381-388 in the CTD (Figure 3), suggesting that these regions are involved in interaction with the additional nucleotides in DNA-L that flank the consensus recognition element.”
§ Mapping Interactions of the Intrinsically Disordered C-Terminal Regions of Tetrameric p53 by Segmental Isotope Labeling and NMR > Abstract
plainstates an association- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption not shown here.
- Also stated in: § The CTD contacts DNA outside the p53 recognition element · hedged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The changes in CTD chemical shifts upon DNA binding are substantially smaller than those for the non-acetylated protein (Figure 7), showing that acetylation of the CTD in the full-length p53 tetramer impairs but does not completely abrogate its interaction with DNA.”
§ Mapping Interactions of the Intrinsically Disordered C-Terminal Regions of Tetrameric p53 by Segmental Isotope Labeling and NMR > Results > Acetylation of the p53 CTD inhibits interactions of the CTD with DNA
plainstates a cause- Asserted: passes — The authors put it forward as true.
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In the paper
“Acetylation of K372, K373, and K382, using a construct of the transcriptional coactivator CBP containing the TAZ2 and acetyltransferase domains, inhibits interaction of the CTD with DNA.”
§ Mapping Interactions of the Intrinsically Disordered C-Terminal Regions of Tetrameric p53 by Segmental Isotope Labeling and NMR > Abstract
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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In the paper
§ Mapping Interactions of the Intrinsically Disordered C-Terminal Regions of Tetrameric p53 by Segmental Isotope Labeling and NMR > Results > The NLS and CTD are disordered in full-length p53
“the disordered NLS (residues 304-325)”
§ Mapping Interactions of the Intrinsically Disordered C-Terminal Regions of Tetrameric p53 by Segmental Isotope Labeling and NMR > Introduction
“nuclear localization signal (NLS, residues 316-325)”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Mapping Interactions of the Intrinsically Disordered C-Terminal Regions of Tetrameric p53 by Segmental Isotope Labeling and NMR > Results > The NLS and CTD are disordered in full-length p53
“CTD (residues 357-393) domains”
§ Mapping Interactions of the Intrinsically Disordered C-Terminal Regions of Tetrameric p53 by Segmental Isotope Labeling and NMR > Introduction
“C-terminal regulatory domain (CTD, residues 364-393)”
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Cited by
TP53 mutations in cancer: Molecular features and therapeutic opportunities (Review)
Tornesello, M. L. (2024) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2024.5448 · Cited by 120
Dynamics and interactions of intrinsically disordered proteins
Arai, M., Suetaka, S., & Ooka, K. (2023) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2023.102734 · Cited by 39
How does p53 work? Regulation by the intrinsically disordered domains
Dyson, H. J., & Wright, P. E. (2024) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2024.10.009 · Cited by 29
Self-citationXu, B., Maimaitijiang, A., Nuerbiyamu, D., Su, Z., & Li, W. (2025) · Biomolecules · doi:10.3390/biom15081088 · Cited by 23
Distinguishing features of fold‐switching proteins
Chakravarty, D., Schafer, J. W., & Porter, L. L. (2023) · Protein Science · doi:10.1002/pro.4596 · Cited by 21
Metadata
- Authors
- Krois, A. S., Park, S., Martinez-Yamout, M. A., Dyson, H. J., & Wright, P. E.
- Affiliations
- Scripps Research Institute (US)
- Department of Integrative Structural and Computational Biology and Skaggs Institute of Chemical Biology, Scripps Research, 10550 North Torrey Pines Road, La Jolla, California92037, United Sates
- Corresponding author
- Wright, Peter E.
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2022-11-16
- Volume
- 61
- Issue
- 23
- Pages
- 2709-2719
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- PMC
- PMC9788666
- OpenAlex
- W4309161821
- Semantic Scholar
- c045343c69d5b0d4a42c7254de45ebcf4ed77812
- Cited by
- 14
- References
- 74
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 2 · 2023: 4
- FWCI
- 0.88
- Type
- journal article
- Language
- en
- Open access
- green
- pmc.ncbi.nlm.nih.gov
- Licence
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA096865)
- National Institute of General Medical Sciences (GM075995, GM131693)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Physical Sciences › Chemistry › Spectroscopy › Advanced NMR Techniques and Applications
- Keywords
- p53, intrinsically disordered regions, C-terminal regulatory domain, tetramerization domain, nuclear localization signal, DNA binding, lysine acetylation, 15N labeling, protein-DNA interactions, tumor suppressor proteins
- MeSH terms
- DNA, Isotope Labeling, Protein Binding, Tumor Suppressor Protein p53, Protein Structure, Tertiary
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
