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Structural Insights into the Autoregulation and Cooperativity of the Human Transcription Factor Ets-2

Ets-2, like its closely related homologue Ets-1, is a member of the Ets family of DNA binding transcription factors. Both proteins are subject to multiple levels of regulation of their DNA binding and transactivation properties. One such regulatory mechanism is the presence of an autoinhibitory modu...

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Autores principales: Newman, Joseph A, Cooper, Christopher D. O., Aitkenhead, Hazel, Gileadi, Opher
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375503/
https://www.ncbi.nlm.nih.gov/pubmed/25670864
http://dx.doi.org/10.1074/jbc.M114.619270
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author Newman, Joseph A
Cooper, Christopher D. O.
Aitkenhead, Hazel
Gileadi, Opher
author_facet Newman, Joseph A
Cooper, Christopher D. O.
Aitkenhead, Hazel
Gileadi, Opher
author_sort Newman, Joseph A
collection PubMed
description Ets-2, like its closely related homologue Ets-1, is a member of the Ets family of DNA binding transcription factors. Both proteins are subject to multiple levels of regulation of their DNA binding and transactivation properties. One such regulatory mechanism is the presence of an autoinhibitory module, which in Ets-1 allosterically inhibits the DNA binding activity. This inhibition can be relieved by interaction with protein partners or cooperative binding to closely separated Ets binding sites in a palindromic arrangement. In this study we describe the 2.5 Å resolution crystal structure of a DNA complex of the Ets-2 Ets domain. The Ets domain crystallized with two distinct species in the asymmetric unit, which closely resemble the autoinhibited and DNA bound forms of Ets-1. This discovery prompted us to re-evaluate the current model for the autoinhibitory mechanism and the structural basis for cooperative DNA binding. In contrast to Ets-1, in which the autoinhibition is caused by a combination of allosteric and steric mechanisms, we were unable to find clear evidence for the allosteric mechanism in Ets-2. We also demonstrated two possibly distinct types of cooperative binding to substrates with Ets binding motifs separated by four and six base pairs and suggest possible molecular mechanisms for this behavior.
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spelling pubmed-43755032015-04-08 Structural Insights into the Autoregulation and Cooperativity of the Human Transcription Factor Ets-2 Newman, Joseph A Cooper, Christopher D. O. Aitkenhead, Hazel Gileadi, Opher J Biol Chem Protein Structure and Folding Ets-2, like its closely related homologue Ets-1, is a member of the Ets family of DNA binding transcription factors. Both proteins are subject to multiple levels of regulation of their DNA binding and transactivation properties. One such regulatory mechanism is the presence of an autoinhibitory module, which in Ets-1 allosterically inhibits the DNA binding activity. This inhibition can be relieved by interaction with protein partners or cooperative binding to closely separated Ets binding sites in a palindromic arrangement. In this study we describe the 2.5 Å resolution crystal structure of a DNA complex of the Ets-2 Ets domain. The Ets domain crystallized with two distinct species in the asymmetric unit, which closely resemble the autoinhibited and DNA bound forms of Ets-1. This discovery prompted us to re-evaluate the current model for the autoinhibitory mechanism and the structural basis for cooperative DNA binding. In contrast to Ets-1, in which the autoinhibition is caused by a combination of allosteric and steric mechanisms, we were unable to find clear evidence for the allosteric mechanism in Ets-2. We also demonstrated two possibly distinct types of cooperative binding to substrates with Ets binding motifs separated by four and six base pairs and suggest possible molecular mechanisms for this behavior. American Society for Biochemistry and Molecular Biology 2015-03-27 2015-02-10 /pmc/articles/PMC4375503/ /pubmed/25670864 http://dx.doi.org/10.1074/jbc.M114.619270 Text en © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Unported License (http://creativecommons.org/licenses/by/3.0/) applies to Author Choice Articles
spellingShingle Protein Structure and Folding
Newman, Joseph A
Cooper, Christopher D. O.
Aitkenhead, Hazel
Gileadi, Opher
Structural Insights into the Autoregulation and Cooperativity of the Human Transcription Factor Ets-2
title Structural Insights into the Autoregulation and Cooperativity of the Human Transcription Factor Ets-2
title_full Structural Insights into the Autoregulation and Cooperativity of the Human Transcription Factor Ets-2
title_fullStr Structural Insights into the Autoregulation and Cooperativity of the Human Transcription Factor Ets-2
title_full_unstemmed Structural Insights into the Autoregulation and Cooperativity of the Human Transcription Factor Ets-2
title_short Structural Insights into the Autoregulation and Cooperativity of the Human Transcription Factor Ets-2
title_sort structural insights into the autoregulation and cooperativity of the human transcription factor ets-2
topic Protein Structure and Folding
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375503/
https://www.ncbi.nlm.nih.gov/pubmed/25670864
http://dx.doi.org/10.1074/jbc.M114.619270
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