title: An intrinsically disordered region of methyl-CpG binding domain protein 2 (MBD2) recruits the histone deacetylase core of the NuRD complex.
abstract: The MBD2-NuRD (Nucleosome Remodeling and Deacetylase) complex is an epigenetic reader of DNA methylation that regulates genes involved in normal development and neoplastic diseases. To delineate the architecture and functional interactions of the MBD2-NuRD complex, we previously solved the structures of MBD2 bound to methylated DNA and a coiled-coil interaction between MBD2 and p66α that recruits the CHD4 nucleosome remodeling protein to the complex. The work presented here identifies novel structural and functional features of a previously uncharacterized domain of MBD2 (MBD2IDR). Biophysical analyses show that the MBD2IDR is an intrinsically disordered region (IDR). However, despite this inherent disorder, MBD2IDR increases the overall binding affinity of MBD2 for methylated DNA. MBD2IDR also recruits the histone deacetylase core components (RbAp48, HDAC2 and MTA2) of NuRD through a critical contact region requiring two contiguous amino acid residues, Arg(286) and Leu(287). Mutating these residues abrogates interaction of MBD2 with the histone deacetylase core and impairs the ability of MBD2 to repress the methylated tumor suppressor gene PRSS8 in MDA-MB-435 breast cancer cells. These findings expand our knowledge of the multi-dimensional interactions of the MBD2-NuRD complex that govern its function.
authors.affiliation: Department of Human and Molecular Genetics and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Megha A
authors.initials: MA
authors.lastname: Desai
authors.affiliation: Department of Pathology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Heather D
authors.initials: HD
authors.lastname: Webb
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Leander M
authors.initials: LM
authors.lastname: Sinanan
authors.affiliation: Institute of Structural Biology and Drug Design, Center for the Study of Biological Complexity, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: J Neel
authors.initials: JN
authors.lastname: Scarsdale
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Ninad M
authors.initials: NM
authors.lastname: Walavalkar
authors.affiliation: Departments of Internal Medicine, Human and Molecular Genetics, and Microbiology and Immunology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA gdginder@vcu.edu.
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Ginder
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA david_willjr@med.unc.edu.
authors.forename: David C
authors.initials: DC
authors.lastname: Williams
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D054730:Protein Interaction Domains and Motifs; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D004268:DNA-Binding Proteins; D064267:Intrinsically Disordered Proteins; C489325:MBD2 protein, human; C489326:Mbd2 protein, mouse; D011994:Recombinant Proteins; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex