Structural Characterization of the SMRT Corepressor Interacting with Histone Deacetylase 7

Abstract The 2525 amino acid SMRT corepressor is an intrinsically disordered hub protein responsible for binding and coordinating the activities of multiple transcription factors and chromatin modifying enzymes. Here we have studied its interaction with HDAC7, a class IIa deacetylase that interacts...

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Autores principales:	Danielle C. Desravines, Itziar Serna Martin, Robert Schneider, Philippe J. Mas, Nataliia Aleksandrova, Malene Ringkjøbing Jensen, Martin Blackledge, Darren J. Hart
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0b8d250e25a8437cb57a64f0045febb5
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spelling	oai:doaj.org-article:0b8d250e25a8437cb57a64f0045febb52021-12-02T15:05:36ZStructural Characterization of the SMRT Corepressor Interacting with Histone Deacetylase 710.1038/s41598-017-03718-52045-2322https://doaj.org/article/0b8d250e25a8437cb57a64f0045febb52017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03718-5https://doaj.org/toc/2045-2322Abstract The 2525 amino acid SMRT corepressor is an intrinsically disordered hub protein responsible for binding and coordinating the activities of multiple transcription factors and chromatin modifying enzymes. Here we have studied its interaction with HDAC7, a class IIa deacetylase that interacts with the corepressor complex together with the highly active class I deacetylase HDAC3. The binding site of class IIa deacetylases was previously mapped to an approximate 500 amino acid region of SMRT, with recent implication of short glycine-serine-isoleucine (GSI) containing motifs. In order to characterize the interaction in detail, we applied a random library screening approach within this region and obtained a range of stable, soluble SMRT fragments. In agreement with an absence of predicted structural domains, these were characterized as intrinsically disordered by NMR spectroscopy. We identified one of them, comprising residues 1255–1452, as interacting with HDAC7 with micromolar affinity. The binding site was mapped in detail by NMR and confirmed by truncation and alanine mutagenesis. Complementing this with mutational analysis of HDAC7, we show that HDAC7, via its surface zinc ion binding site, binds to a 28 residue stretch in SMRT comprising a GSI motif followed by an alpha helix.Danielle C. DesravinesItziar Serna MartinRobert SchneiderPhilippe J. MasNataliia AleksandrovaMalene Ringkjøbing JensenMartin BlackledgeDarren J. HartNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Danielle C. Desravines Itziar Serna Martin Robert Schneider Philippe J. Mas Nataliia Aleksandrova Malene Ringkjøbing Jensen Martin Blackledge Darren J. Hart Structural Characterization of the SMRT Corepressor Interacting with Histone Deacetylase 7
description	Abstract The 2525 amino acid SMRT corepressor is an intrinsically disordered hub protein responsible for binding and coordinating the activities of multiple transcription factors and chromatin modifying enzymes. Here we have studied its interaction with HDAC7, a class IIa deacetylase that interacts with the corepressor complex together with the highly active class I deacetylase HDAC3. The binding site of class IIa deacetylases was previously mapped to an approximate 500 amino acid region of SMRT, with recent implication of short glycine-serine-isoleucine (GSI) containing motifs. In order to characterize the interaction in detail, we applied a random library screening approach within this region and obtained a range of stable, soluble SMRT fragments. In agreement with an absence of predicted structural domains, these were characterized as intrinsically disordered by NMR spectroscopy. We identified one of them, comprising residues 1255–1452, as interacting with HDAC7 with micromolar affinity. The binding site was mapped in detail by NMR and confirmed by truncation and alanine mutagenesis. Complementing this with mutational analysis of HDAC7, we show that HDAC7, via its surface zinc ion binding site, binds to a 28 residue stretch in SMRT comprising a GSI motif followed by an alpha helix.
format	article
author	Danielle C. Desravines Itziar Serna Martin Robert Schneider Philippe J. Mas Nataliia Aleksandrova Malene Ringkjøbing Jensen Martin Blackledge Darren J. Hart
author_facet	Danielle C. Desravines Itziar Serna Martin Robert Schneider Philippe J. Mas Nataliia Aleksandrova Malene Ringkjøbing Jensen Martin Blackledge Darren J. Hart
author_sort	Danielle C. Desravines
title	Structural Characterization of the SMRT Corepressor Interacting with Histone Deacetylase 7
title_short	Structural Characterization of the SMRT Corepressor Interacting with Histone Deacetylase 7
title_full	Structural Characterization of the SMRT Corepressor Interacting with Histone Deacetylase 7
title_fullStr	Structural Characterization of the SMRT Corepressor Interacting with Histone Deacetylase 7
title_full_unstemmed	Structural Characterization of the SMRT Corepressor Interacting with Histone Deacetylase 7
title_sort	structural characterization of the smrt corepressor interacting with histone deacetylase 7
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/0b8d250e25a8437cb57a64f0045febb5
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Structural Characterization of the SMRT Corepressor Interacting with Histone Deacetylase 7

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