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

Kurt A. Swanson; Paul S. Knoepfler; Kai Huang; Richard S. Kang; Shaun M. Cowley; Carol D. Laherty; Robert N. Eisenman; Ishwar Radhakrishnan

doi:10.1038/nsmb798

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

Kurt A. Swanson, Paul S. Knoepfler, Kai Huang, Richard S. Kang, Shaun M. Cowley, Carol D. Laherty, Robert N. Eisenman^*, Ishwar Radhakrishnan

^*Corresponding author for this work

Robert H. Lurie Comprehensive Cancer Center

Research output: Contribution to journal › Article › peer-review

62 Scopus citations

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.

Original language	English (US)
Pages (from-to)	738-746
Number of pages	9
Journal	Nature Structural and Molecular Biology
Volume	11
Issue number	8
DOIs	https://doi.org/10.1038/nsmb798
State	Published - Aug 2004

Funding

We thank M. Adams for assistance with pull-down assays. This work was supported by funds from the March of Dimes Birth Defects Foundation (no. 5-FY00-605) and the US National Institutes of Health (NIH) (GM 64715) to I.R. and by funds from the NIH (CA 57138) and an American Cancer Society research professorship to R.N.E. K.A.S. was supported by an NIH molecular biophysics training grant and P.S.K. is a special fellow of the Leukemia and Lymphoma Society. We are grateful to the Lurie Comprehensive Cancer Center for supporting structural biology research at Northwestern and the Keck Biophysics Facility for access to instrumentation.

ASJC Scopus subject areas

Molecular Biology
Structural Biology

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10.1038/nsmb798

Cite this

@article{f4939360311849ef83d91fe6b50125da,

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.",

author = "Swanson, {Kurt A.} and Knoepfler, {Paul S.} and Kai Huang and Kang, {Richard S.} and Cowley, {Shaun M.} and Laherty, {Carol D.} and Eisenman, {Robert N.} and Ishwar Radhakrishnan",

note = "Funding Information: We thank M. Adams for assistance with pull-down assays. This work was supported by funds from the March of Dimes Birth Defects Foundation (no. 5-FY00-605) and the US National Institutes of Health (NIH) (GM 64715) to I.R. and by funds from the NIH (CA 57138) and an American Cancer Society research professorship to R.N.E. K.A.S. was supported by an NIH molecular biophysics training grant and P.S.K. is a special fellow of the Leukemia and Lymphoma Society. We are grateful to the Lurie Comprehensive Cancer Center for supporting structural biology research at Northwestern and the Keck Biophysics Facility for access to instrumentation.",

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AU - Cowley, Shaun M.

AU - Laherty, Carol D.

AU - Eisenman, Robert N.

AU - Radhakrishnan, Ishwar

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N2 - 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.

AB - 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.

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

Abstract

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Solution Structure of HBP1 SID-mSin3A PAH2 Complex

Solution Structure of Mad1 SID-mSin3A PAH2 Complex

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

Abstract

Funding

ASJC Scopus subject areas

Access to Document

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Datasets

Solution Structure of HBP1 SID-mSin3A PAH2 Complex

Solution Structure of Mad1 SID-mSin3A PAH2 Complex

Cite this