title: HBP1 and Mad1 repressors bind the Sin3 corepressor PAH2 domain with opposite helical orientations.
abstract: Recruitment of the histone deacetylase (HDAC)-associated Sin3 corepressor is an obligatory step in many eukaryotic gene silencing pathways. Here we show that HBP1, a cell cycle inhibitor and regulator of differentiation, represses transcription in a HDAC/Sin3-dependent manner by targeting the mammalian Sin3A (mSin3A) PAH2 domain. HBP1 is unrelated to the Mad1 repressor for which high-resolution structures in complex with PAH2 have been described. We show that like Mad1, the HBP1 transrepression domain binds through a helical structure to the hydrophobic cleft of mSin3A PAH2. Notably, the HBP1 helix binds PAH2 in a reversed orientation relative to Mad1 and, equally unexpectedly, this is correlated with a chain reversal of the minimal Sin3 interaction motifs. These results not only provide insights into how multiple, unrelated transcription factors recruit the same coregulator, but also have implications for how sequence similarity searches are conducted.
authors.affiliation: Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, Illinois 60208-3500, USA.
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Swanson
authors.forename: Paul S
authors.initials: PS
authors.lastname: Knoepfler
authors.forename: Kai
authors.initials: K
authors.lastname: Huang
authors.forename: Richard S
authors.initials: RS
authors.lastname: Kang
authors.forename: Shaun M
authors.initials: SM
authors.lastname: Cowley
authors.forename: Carol D
authors.initials: CD
authors.lastname: Laherty
authors.forename: Robert N
authors.initials: RN
authors.lastname: Eisenman
authors.forename: Ishwar
authors.initials: I
authors.lastname: Radhakrishnan
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002151:Calorimetry; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002460:Cell Line; D005982:Glutathione Transferase / Q000378:metabolism; D006609:High Mobility Group Proteins / Q000378:metabolism*; D006655:Histone Deacetylases; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013237:Stereoisomerism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D020798:Two-Hybrid System Techniques
chemical_list: D018797:Cell Cycle Proteins; C486328:HBP1 protein, human; D006609:High Mobility Group Proteins; C501382:MAD1 protein, S cerevisiae; C501384:MAD1L1 protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins; C071731:SIN3 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D005982:Glutathione Transferase; D006655:Histone Deacetylases