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Structural plasticity of methyllysine recognition by the tandem tudor domain of 53BP1.

Tong Q, Cui G, Botuyan MV, Rothbart SB, Hayashi R, Musselman CA, Singh N, Appella E, Strahl BD, Mer G, Kutateladze TG
Structure 23 312-21 (2015)
Cited: 26 times
EuropePMC logo PMID: 25579814

Abstract

p53 is dynamically regulated through various posttranslational modifications (PTMs), which differentially modulate its function and stability. The dimethylated marks p53K370me2 and p53K382me2 are associated with p53 activation or stabilization and both are recognized by the tandem Tudor domain (TTD) of 53BP1, a p53 cofactor. Here we detail the molecular mechanisms for the recognition of p53K370me2 and p53K382me2 by 53BP1. The solution structures of TTD in complex with the p53K370me2 and p53K382me2 peptides show a remarkable plasticity of 53BP1 in accommodating these diverse dimethyllysine-containing sequences. We demonstrate that dimeric TTDs are capable of interacting with the two PTMs on a single p53K370me2K382me2 peptide, greatly strengthening the 53BP1-p53 interaction. Analysis of binding affinities of TTD toward methylated p53 and histones reveals strong preference of 53BP1 for p53K382me2, H4K20me2, and H3K36me2 and suggests a possible role of multivalent contacts of 53BP1 in p53 targeting to and accumulation at the sites of DNA damage.

Reviews - 2mwp mentioned but not cited (2)

  1. p53 Proteoforms and Intrinsic Disorder: An Illustration of the Protein Structure-Function Continuum Concept. Uversky VN. Int J Mol Sci 17 E1874 (2016)
  2. 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)

Articles - 2mwp mentioned but not cited (1)



Reviews citing this publication (8)

  1. Targeting p53 pathways: mechanisms, structures, and advances in therapy. Wang H, Guo M, Wei H, Chen Y. Signal Transduct Target Ther 8 92 (2023)
  2. DOT1L and H3K79 Methylation in Transcription and Genomic Stability. Wood K, Tellier M, Murphy S. Biomolecules 8 E11 (2018)
  3. The upstreams and downstreams of H3K79 methylation by DOT1L. Vlaming H, van Leeuwen F. Chromosoma 125 593-605 (2016)
  4. Reading chromatin signatures after DNA double-strand breaks. Wilson MD, Durocher D. Philos Trans R Soc Lond B Biol Sci 372 20160280 (2017)
  5. 53BP1: Keeping It under Control, Even at a Distance from DNA Damage. Rass E, Willaume S, Bertrand P. Genes (Basel) 13 2390 (2022)
  6. A role of the 53BP1 protein in genome protection: structural and functional characteristics of 53BP1-dependent DNA repair. Bártová E, Legartová S, Dundr M, Suchánková J. Aging (Albany NY) 11 2488-2511 (2019)
  7. Methyllysine binding domains: Structural insight and small molecule probe development. Teske KA, Hadden MK. Eur J Med Chem 136 14-35 (2017)
  8. Regulation of p53 Function by Formation of Non-Nuclear Heterologous Protein Complexes. Zavileyskiy L, Bunik V. Biomolecules 12 327 (2022)

Articles citing this publication (15)



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