title: Multivalent Histone and DNA Engagement by a PHD/BRD/PWWP Triple Reader Cassette Recruits ZMYND8 to K14ac-Rich Chromatin.
abstract: Elucidation of interactions involving DNA and histone post-translational-modifications (PTMs) is essential for providing insights into complex biological functions. Reader assemblies connected by flexible linkages facilitate avidity and increase affinity; however, little is known about the contribution to the recognition process of multiple PTMs because of rigidity in the absence of conformational flexibility. Here, we resolve the crystal structure of the triple reader module (PHD-BRD-PWWP) of ZMYND8, which forms a stable unit capable of simultaneously recognizing multiple histone PTMs while presenting a charged platform for association with DNA. Single domain disruptions destroy the functional network of interactions initiated by ZMYND8, impairing recruitment to sites of DNA damage. Our data establish a proof of principle that rigidity can be compensated by concomitant DNA and histone PTM interactions, maintaining multivalent engagement of transient chromatin states. Thus, our findings demonstrate an important role for rigid multivalent reader modules in nucleosome binding and chromatin function.
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Pavel
authors.initials: P
authors.lastname: Savitsky
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Tobias
authors.initials: T
authors.lastname: Krojer
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Takao
authors.initials: T
authors.lastname: Fujisawa
authors.affiliation: Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, 600 University Ave., Toronto, ON M5G 1X5, Canada.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Lambert
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Picaud
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Chen-Yi
authors.initials: CY
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Erin K
authors.initials: EK
authors.lastname: Shanle
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Krajewski
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Hans
authors.initials: H
authors.lastname: Friedrichsen
authors.affiliation: Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kanapin
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Goding
authors.affiliation: Structural Genomics Consortium, MaRS Centre, South Tower, 101 College St., Suite 700, Toronto, ON M5G 1L7 Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Schapira
authors.affiliation: Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Samsonova
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Strahl
authors.affiliation: Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, 600 University Ave., Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gingras
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK; Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building Roosevelt Drive, Oxford OX3 7DQ, UK. Electronic address: panagis.filippakopoulos@sgc.ox.ac.uk.
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
mesh_terms: D002843:Chromatin / Q000235:genetics*; D018360:Crystallography, X-Ray; D004249:DNA Damage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry; D006657:Histones / Q000737:chemistry / Q000235:genetics; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics*; D009707:Nucleosomes / Q000737:chemistry / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D000072417:Protein Domains / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics*
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; D046912:Multiprotein Complexes; D009707:Nucleosomes; D025521:Tumor Suppressor Proteins; C000617312:ZMYND8 protein, human
keywords: DNA damage; chromatin binding; histone marks; masking of chromatin binding; multivalency; plasticity; protein network assembly; structural rigidity