Molecular mechanism of thermosensory function of human heat shock transcription factor Hsf1

The heat shock response is a universal homeostatic cell autonomous reaction of organisms to cope with adverse environmental conditions. In mammalian cells, this response is mediated by the heat shock transcription factor Hsf1, which is monomeric in unstressed cells and upon activation trimerizes, an...

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Autores principales: Hentze, Nikolai, Le Breton, Laura, Wiesner, Jan, Kempf, Georg, Mayer, Matthias P
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775227/
https://www.ncbi.nlm.nih.gov/pubmed/26785146
http://dx.doi.org/10.7554/eLife.11576
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author Hentze, Nikolai
Le Breton, Laura
Wiesner, Jan
Kempf, Georg
Mayer, Matthias P
author_facet Hentze, Nikolai
Le Breton, Laura
Wiesner, Jan
Kempf, Georg
Mayer, Matthias P
author_sort Hentze, Nikolai
collection PubMed
description The heat shock response is a universal homeostatic cell autonomous reaction of organisms to cope with adverse environmental conditions. In mammalian cells, this response is mediated by the heat shock transcription factor Hsf1, which is monomeric in unstressed cells and upon activation trimerizes, and binds to promoters of heat shock genes. To understand the basic principle of Hsf1 activation we analyzed temperature-induced alterations in the conformational dynamics of Hsf1 by hydrogen exchange mass spectrometry. We found a temperature-dependent unfolding of Hsf1 in the regulatory region happening concomitant to tighter packing in the trimerization region. The transition to the active DNA binding-competent state occurred highly cooperative and was concentration dependent. Surprisingly, Hsp90, known to inhibit Hsf1 activation, lowered the midpoint temperature of trimerization and reduced cooperativity of the process thus widening the response window. Based on our data we propose a kinetic model of Hsf1 trimerization. DOI: http://dx.doi.org/10.7554/eLife.11576.001
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spelling pubmed-47752272016-03-07 Molecular mechanism of thermosensory function of human heat shock transcription factor Hsf1 Hentze, Nikolai Le Breton, Laura Wiesner, Jan Kempf, Georg Mayer, Matthias P eLife Biochemistry The heat shock response is a universal homeostatic cell autonomous reaction of organisms to cope with adverse environmental conditions. In mammalian cells, this response is mediated by the heat shock transcription factor Hsf1, which is monomeric in unstressed cells and upon activation trimerizes, and binds to promoters of heat shock genes. To understand the basic principle of Hsf1 activation we analyzed temperature-induced alterations in the conformational dynamics of Hsf1 by hydrogen exchange mass spectrometry. We found a temperature-dependent unfolding of Hsf1 in the regulatory region happening concomitant to tighter packing in the trimerization region. The transition to the active DNA binding-competent state occurred highly cooperative and was concentration dependent. Surprisingly, Hsp90, known to inhibit Hsf1 activation, lowered the midpoint temperature of trimerization and reduced cooperativity of the process thus widening the response window. Based on our data we propose a kinetic model of Hsf1 trimerization. DOI: http://dx.doi.org/10.7554/eLife.11576.001 eLife Sciences Publications, Ltd 2016-01-19 /pmc/articles/PMC4775227/ /pubmed/26785146 http://dx.doi.org/10.7554/eLife.11576 Text en © 2016, Hentze et al http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry
Hentze, Nikolai
Le Breton, Laura
Wiesner, Jan
Kempf, Georg
Mayer, Matthias P
Molecular mechanism of thermosensory function of human heat shock transcription factor Hsf1
title Molecular mechanism of thermosensory function of human heat shock transcription factor Hsf1
title_full Molecular mechanism of thermosensory function of human heat shock transcription factor Hsf1
title_fullStr Molecular mechanism of thermosensory function of human heat shock transcription factor Hsf1
title_full_unstemmed Molecular mechanism of thermosensory function of human heat shock transcription factor Hsf1
title_short Molecular mechanism of thermosensory function of human heat shock transcription factor Hsf1
title_sort molecular mechanism of thermosensory function of human heat shock transcription factor hsf1
topic Biochemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775227/
https://www.ncbi.nlm.nih.gov/pubmed/26785146
http://dx.doi.org/10.7554/eLife.11576
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