title: An acetyl-methyl switch drives a conformational change in p53.
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.
authors: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors: Qiong
authors: Q
authors: Tong
authors: Laboratory of Cell Biology, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors: Sharlyn J
authors: SJ
authors: Mazur
authors: Basic Science Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors: Hector
authors: H
authors: Rincon-Arano
authors: Department of Biochemistry and Biophysics and the Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors: Scott B
authors: SB
authors: Rothbart
authors: Department of Chemistry and Biochemistry, University of Denver, Denver, CO 80210, USA.
authors: Dmitry M
authors: DM
authors: Kuznetsov
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors: Gaofeng
authors: G
authors: Cui
authors: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors: Wallace H
authors: WH
authors: Liu
authors: Laboratory of Cell Biology, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors: Yantenew
authors: Y
authors: Gete
authors: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors: Brianna J
authors: BJ
authors: Klein
authors: Laboratory of Cell Biology, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors: Lisa
authors: L
authors: Jenkins
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors: Georges
authors: G
authors: Mer
authors: Department of Chemistry and Biochemistry, University of Denver, Denver, CO 80210, USA.
authors: Andrei G
authors: AG
authors: Kutateladze
authors: Department of Biochemistry and Biophysics and the Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors: Brian D
authors: BD
authors: Strahl
authors: Basic Science Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Radiation Oncology, University Washington School of Medicine, Seattle, WA 98109, USA.
authors: Mark
authors: M
authors: Groudine
authors: Laboratory of Cell Biology, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors: Ettore
authors: E
authors: Appella
authors: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA. Electronic address: tatiana.kutateladze@ucdenver.edu.
authors: Tatiana G
authors: TG
authors: Kutateladze
mesh_terms: D018360:Crystallography, X-Ray; D004249:DNA Damage / Q000502:physiology; D019175:DNA Methylation / Q000235:genetics*; D006801:Humans; D008024:Ligands; D008239:Lysine / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D008024:Ligands; D016159:Tumor Suppressor Protein p53; D008239:Lysine
references: J Biol Chem. 2010 Nov 26;285(48):37725-32
references: 20870725
references: Mol Cell. 2007 Aug 17;27(4):636-46
references: 17707234
references: Mol Biol Cell. 2005 Apr;16(4):1684-95
references: 15659650
references: Cell. 2006 Dec 29;127(7):1361-73
references: 17190600
references: Cell Cycle. 2008 Jan 15;7(2):222-31
references: 18264029
references: Nature. 2004 Nov 18;432(7015):406-11
references: 15525939
references: Nature. 2004 Nov 18;432(7015):353-60
references: 15525938
references: Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2259-64
references: 14982997
references: Mol Cell. 2008 May 9;30(3):277-89
references: 18471974
references: Mol Cell. 2004 Jan 30;13(2):251-63
references: 14759370
references: Structure. 2008 Apr;16(4):643-52
references: 18400184
references: Mol Cell. 2001 Dec;8(6):1243-54
references: 11779500
references: Nature. 2012 Sep 6;489(7414):57-74
references: 22955616
references: J Mol Biol. 2010 May 14;398(4):489-96
references: 20307547
references: Mol Cell Biol. 2007 Oct;27(19):6756-69
references: 17646389
references: Mol Cell. 2012 Apr 13;46(1):30-42
references: 22387025
references: Cell. 2010 Jul 9;142(1):89-100
references: 20598361
references: J Biol Chem. 2009 Apr 24;284(17):11171-83
references: 19265193
references: J Biol Chem. 2008 Dec 12;283(50):34660-6
references: 18840612
references: Cell. 2008 May 16;133(4):612-26
references: 18485870
references: Nat Struct Mol Biol. 2013 Mar;20(3):317-25
references: 23377543
references: Trends Mol Med. 2010 Nov;16(11):528-36
references: 20932800
references: J Biol Chem. 2006 Jan 20;281(3):1394-400
references: 16291740
references: Cell. 2010 Jul 9;142(1):17-9
references: 20603009
references: Mol Cell. 2008 Feb 15;29(3):392-400
references: 18280244
references: J Biol Chem. 2007 Jan 19;282(3):1797-804
references: 17098746
references: J Biol Chem. 2009 Feb 20;284(8):5158-64
references: 19106109
references: Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):69-74
references: 20018659
references: Nature. 2007 Sep 6;449(7158):105-8
references: 17805299
references: Mol Cell Proteomics. 2014 Jan;13(1):1-17
references: 24056736
references: Nature. 2006 Nov 30;444(7119):629-32
references: 17108971
references: J Biol Chem. 2010 Mar 26;285(13):9636-41
references: 20118233
references: Curr Opin Genet Dev. 2008 Apr;18(2):152-8
references: 18339539
references: J Mol Cell Biol. 2013 Jun;5(3):157-65
references: 23329852
references: J Biol Chem. 2011 Jul 15;286(28):25076-87
references: 21586571
references: Nat Struct Mol Biol. 2012 Sep;19(9):916-24
references: 22864287