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Structure. 2015 Feb 3;23(2):312-21. doi: 10.1016/j.str.2014.11.013. Epub 2015 Jan 8.

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

Author information

1
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
2
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
3
Department of Biochemistry and Biophysics and the Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
4
Laboratory of Cell Biology, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
5
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: mer.georges@mayo.edu.
6
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA. Electronic address: tatiana.kutateladze@ucdenver.edu.

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.

PMID:
25579814
PMCID:
PMC4321732
DOI:
10.1016/j.str.2014.11.013
[Indexed for MEDLINE]
Free PMC Article

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