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An acetyl-methyl switch drives a conformational change in p53.

Tong Q, Mazur SJ, Rincon-Arano H, Rothbart SB, Kuznetsov DM, Cui G, Liu WH, Gete Y, Klein BJ, Jenkins L, Mer G, Kutateladze AG, Strahl BD, Groudine M, Appella E, Kutateladze TG
Structure 23 322-31 (2015)
Cited: 17 times
EuropePMC logo PMID: 25651062

Abstract

Individual posttranslational modifications (PTMs) of p53 mediate diverse p53-dependent responses; however, much less is known about the combinatorial action of adjacent modifications. Here, we describe crosstalk between the early DNA damage response mark p53K382me2 and the surrounding PTMs that modulate binding of p53 cofactors, including 53BP1 and p300. The 1.8 Å resolution crystal structure of the tandem Tudor domain (TTD) of 53BP1 in complex with p53 peptide acetylated at K381 and dimethylated at K382 (p53K381acK382me2) reveals that the dual PTM induces a conformational change in p53. The α-helical fold of p53K381acK382me2 positions the side chains of R379, K381ac, and K382me2 to interact with TTD concurrently, reinforcing a modular design of double PTM mimetics. Biochemical and nuclear magnetic resonance analyses show that other surrounding PTMs, including phosphorylation of serine/threonine residues of p53, affect association with TTD. Our findings suggest a novel PTM-driven conformation switch-like mechanism that may regulate p53 interactions with binding partners.

Reviews - 4x34 mentioned but not cited (1)

  1. p53 Proteoforms and Intrinsic Disorder: An Illustration of the Protein Structure-Function Continuum Concept. Uversky VN. Int J Mol Sci 17 E1874 (2016)

Articles - 4x34 mentioned but not cited (2)

  1. An acetyl-methyl switch drives a conformational change in p53. Tong Q, Mazur SJ, Rincon-Arano H, Rothbart SB, Kuznetsov DM, Cui G, Liu WH, Gete Y, Klein BJ, Jenkins L, Mer G, Kutateladze AG, Strahl BD, Groudine M, Appella E, Kutateladze TG. Structure 23 322-331 (2015)
  2. Design and Construction of a Focused DNA-Encoded Library for Multivalent Chromatin Reader Proteins. Rectenwald JM, Guduru SKR, Dang Z, Collins LB, Liao YE, Norris-Drouin JL, Cholensky SH, Kaufmann KW, Hammond SM, Kireev DB, Frye SV, Pearce KH. Molecules 25 E979 (2020)


Reviews citing this publication (8)

  1. The p53 Pathway: Origins, Inactivation in Cancer, and Emerging Therapeutic Approaches. Joerger AC, Fersht AR. Annu Rev Biochem 85 375-404 (2016)
  2. Mechanisms of transcriptional regulation by p53. Sullivan KD, Galbraith MD, Andrysik Z, Espinosa JM. Cell Death Differ 25 133-143 (2018)
  3. p53 shades of Hippo. Furth N, Aylon Y, Oren M. Cell Death Differ 25 81-92 (2018)
  4. The Tail That Wags the Dog: How the Disordered C-Terminal Domain Controls the Transcriptional Activities of the p53 Tumor-Suppressor Protein. Laptenko O, Tong DR, Manfredi J, Prives C. Trends Biochem Sci 41 1022-1034 (2016)
  5. Protein function machinery: from basic structural units to modulation of activity. Berezovsky IN, Guarnera E, Zheng Z, Eisenhaber B, Eisenhaber F. Curr Opin Struct Biol 42 67-74 (2017)
  6. Reading between the Lines: "ADD"-ing Histone and DNA Methylation Marks toward a New Epigenetic "Sum". Noh KM, Allis CD, Li H. ACS Chem Biol 11 554-563 (2016)
  7. Regulation of p53 Function by Formation of Non-Nuclear Heterologous Protein Complexes. Zavileyskiy L, Bunik V. Biomolecules 12 327 (2022)
  8. Peptide and protein chemistry approaches to study the tumor suppressor protein p53. Chatterjee C, Singh SK. Org Biomol Chem 20 5500-5509 (2022)

Articles citing this publication (6)

  1. Effects of Acetylation and Phosphorylation on Subunit Interactions in Three Large Eukaryotic Complexes. Šoštarić N, O'Reilly FJ, Giansanti P, Heck AJR, Gavin AC, van Noort V. Mol Cell Proteomics 17 2387-2401 (2018)
  2. A Chromatin-Focused siRNA Screen for Regulators of p53-Dependent Transcription. Sammons MA, Zhu J, Berger SL. G3 (Bethesda) 6 2671-2678 (2016)
  3. Molecular dynamics shows complex interplay and long-range effects of post-translational modifications in yeast protein interactions. Šoštarić N, van Noort V. PLoS Comput Biol 17 e1008988 (2021)
  4. Mapping Interactions of the Intrinsically Disordered C-Terminal Regions of Tetrameric p53 by Segmental Isotope Labeling and NMR. Krois AS, Park S, Martinez-Yamout MA, Dyson HJ, Wright PE. Biochemistry 61 2709-2719 (2022)
  5. Mass Spectrometry-Based Strategies for Assessing Human Exposure Using Hemoglobin Adductomics. Rajczewski AT, Ndreu L, Vryonidis E, Hurben AK, Jamshidi S, Griffin TJ, Törnqvist MÅ, Tretyakova NY, Karlsson I. Chem Res Toxicol 36 2019-2030 (2023)
  6. Most Probable Druggable Pockets in Mutant p53-Arg175His Clusters Extracted from Gaussian Accelerated Molecular Dynamics Simulations. Mustafa M, Gharaibeh M. Protein J 41 27-43 (2022)


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