title: Insights into the Recruitment of Class IIa Histone Deacetylases (HDACs) to the SMRT/NCoR Transcriptional Repression Complex.
abstract: Class IIa histone deacetylases repress transcription of target genes. However, their mechanism of action is poorly understood because they exhibit very low levels of deacetylase activity. The class IIa HDACs are associated with the SMRT/NCoR repression complexes and this may, at least in part, account for their repressive activity. However, the molecular mechanism of recruitment to co-repressor proteins has yet to be established. Here we show that a repeated peptide motif present in both SMRT and NCoR is sufficient to mediate specific interaction, with micromolar affinity, with all the class IIa HDACs (HDACs 4, 5, 7, and 9). Mutations in the consensus motif abrogate binding. Mutational analysis of HDAC4 suggests that the peptide interacts in the vicinity of the active site of the enzyme and requires the "closed" conformation of the zinc-binding loop on the surface of the enzyme. Together these findings represent the first insights into the molecular mechanism of recruitment of class IIa HDACs to the SMRT/NCoR repression complexes.
authors.affiliation: Department of Biochemistry, Henry Wellcome Laboratories of Structural Biology, University of Leicester, Leicester LE1 9HN.
authors.forename: Gregg M
authors.initials: GM
authors.lastname: Hudson
authors.affiliation: Department of Biochemistry, Henry Wellcome Laboratories of Structural Biology, University of Leicester, Leicester LE1 9HN.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Watson
authors.affiliation: Department of Biochemistry, Henry Wellcome Laboratories of Structural Biology, University of Leicester, Leicester LE1 9HN.
authors.forename: Louise
authors.initials: L
authors.lastname: Fairall
authors.affiliation: Department of Chemistry, University of Leicester, Leicester LE1 7RH, United Kingdom.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Jamieson
authors.affiliation: Department of Biochemistry, Henry Wellcome Laboratories of Structural Biology, University of Leicester, Leicester LE1 9HN. Electronic address: john.schwabe@le.ac.uk.
authors.forename: John W R
authors.initials: JWR
authors.lastname: Schwabe
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D056985:Nuclear Receptor Co-Repressor 2 / Q000737:chemistry / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D060066:Protein Interaction Maps; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: C539130:NCOR2 protein, human; D056985:Nuclear Receptor Co-Repressor 2; D012097:Repressor Proteins; C400300:HDAC4 protein, human; D006655:Histone Deacetylases
keywords: epigenetics; histone acetylation; histone deacetylase 4 (HDAC4); protein-protein interaction; transcription corepressor