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HBP1 and Mad1 repressors bind the Sin3 corepressor PAH2 domain with opposite helical orientations.

Swanson, Kurt A and Knoepfler, Paul S and Huang, Kai and Kang, Richard S and Cowley, Shaun M and Laherty, Carol D and Eisenman, Robert N and Radhakrishnan, Ishwar (2004) HBP1 and Mad1 repressors bind the Sin3 corepressor PAH2 domain with opposite helical orientations. Nature structural & molecular biology, 11 (8). pp. 738-746. ISSN 1545-9993

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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.

Item Type: Article or Abstract
Additional Information: This article is available to subscribers only at the Article URL above.
DOI: 10.1038/nsmb798
PubMed ID: 15235594
Grant Numbers: 5-FY00-605, GM 64715, CA 57138
Keywords or MeSH Headings: Amino Acid Motifs; Amino Acid Sequence; Calorimetry; Cell Cycle Proteins; Cell Differentiation; Cell Line; Glutathione Transferase/metabolism; High Mobility Group Proteins/metabolism; Humans; Magnetic Resonance Spectroscopy; Microscopy, Fluorescence; Models, Molecular; Molecular Sequence Data; Nuclear Proteins; Phosphoproteins/metabolism; Precipitin Tests; Protein Binding; Protein Structure, Tertiary; Repressor Proteins/metabolism; Saccharomyces cerevisiae Proteins/metabolism; Sequence Homology, Amino Acid; Stereoisomerism; Transcription Factors/metabolism; Transcription, Genetic; Transfection; Two-Hybrid System Techniques;
Subjects: Molecules > Proteins > Transcription factors
Molecules > Molecular structure
Cellular and Organismal Processes > Genetic processes > Transcription
Depositing User: Library Staff
Date Deposited: 16 Dec 2008 17:50
Last Modified: 13 May 2010 21:21

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