title: Structural plasticity of methyllysine recognition by the tandem tudor domain of 53BP1.
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.
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Tong
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Cui
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Maria Victoria
authors.initials: MV
authors.lastname: Botuyan
authors.affiliation: Department of Biochemistry and Biophysics and the Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Rothbart
authors.affiliation: Laboratory of Cell Biology, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Ryo
authors.initials: R
authors.lastname: Hayashi
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Musselman
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Namit
authors.initials: N
authors.lastname: Singh
authors.affiliation: Laboratory of Cell Biology, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Ettore
authors.initials: E
authors.lastname: Appella
authors.affiliation: Department of Biochemistry and Biophysics and the Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Strahl
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: mer.georges@mayo.edu.
authors.forename: Georges
authors.initials: G
authors.lastname: Mer
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA. Electronic address: tatiana.kutateladze@ucdenver.edu.
authors.forename: Tatiana G
authors.initials: TG
authors.lastname: Kutateladze
mesh_terms: D000595:Amino Acid Sequence; D019175:DNA Methylation / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism; D008239:Lysine / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D008239:Lysine