title: Structural insights into the assembly of the histone deacetylase-associated Sin3L/Rpd3L corepressor complex.
abstract: Acetylation is correlated with chromatin decondensation and transcriptional activation, but its regulation by histone deacetylase (HDAC)-bearing corepressor complexes is poorly understood. Here, we describe the mechanism of assembly of the mammalian Sin3L/Rpd3L complex facilitated by Sds3, a conserved subunit deemed critical for proper assembly. Sds3 engages a globular, helical region of the HDAC interaction domain (HID) of the scaffolding protein Sin3A through a bipartite motif comprising a helix and an adjacent extended segment. Sds3 dimerizes through not only one of the predicted coiled-coil motifs but also, the segment preceding it, forming an ∼ 150-Å-long antiparallel dimer. Contrary to previous findings in yeast, Sin3A rather than Sds3 functions in recruiting HDAC1 into the complex by engaging the latter through a highly conserved segment adjacent to the helical HID subdomain. In the resulting model for the ternary complex, the two copies of the HDACs are situated distally and dynamically because of a natively unstructured linker connecting the dimerization domain and the Sin3A interaction domain of Sds3; these features contrast with the static organization described previously for the NuRD (nucleosome remodeling and deacetylase) complex. The Sds3 linker features several conserved basic residues that could potentially maintain the complex on chromatin by nonspecific interactions with DNA after initial recruitment by sequence-specific DNA-binding repressors.
authors.affiliation: Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208-3500;
authors.forename: Michael D
authors.initials: MD
authors.lastname: Clark
authors.affiliation: Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208-3500;
authors.forename: Ryan
authors.initials: R
authors.lastname: Marcum
authors.affiliation: Department of Pharmacology, New York University School of Medicine, New York City, NY 10016.
authors.forename: Richard
authors.initials: R
authors.lastname: Graveline
authors.affiliation: Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208-3500;
authors.forename: Clarence W
authors.initials: CW
authors.lastname: Chan
authors.affiliation: Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208-3500;
authors.forename: Tao
authors.initials: T
authors.lastname: Xie
authors.affiliation: Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208-3500;
authors.forename: Zhonglei
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208-3500;
authors.forename: Yujia
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208-3500;
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208-3500;
authors.forename: Alfonso
authors.initials: A
authors.lastname: Mondragón
authors.affiliation: Department of Pharmacology, New York University School of Medicine, New York City, NY 10016.
authors.forename: Gregory
authors.initials: G
authors.lastname: David
authors.affiliation: Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208-3500; i-radhakrishnan@northwestern.edu.
authors.forename: Ishwar
authors.initials: I
authors.lastname: Radhakrishnan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019281:Dimerization; D006655:Histone Deacetylases / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D011487:Protein Conformation; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D012097:Repressor Proteins; D006655:Histone Deacetylases
keywords: corepressor complex; histone deacetylase; protein–protein interaction; structural biology; transcription repression