Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation

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Zheng, Xu
Krakowiak, Joanna
Patel, Nikit
Beyzavi, Ali
Ezike, Jideofor
Pincus, David
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https://doi.org/10.7554/eLife.18638Metadata
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Zheng, Xu, Joanna Krakowiak, Nikit Patel, Ali Beyzavi, Jideofor Ezike, Ahmad S Khalil, and David Pincus. 2016. “Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation.” eLife 5 (1): e18638. doi:10.7554/eLife.18638. http://dx.doi.org/10.7554/eLife.18638.Abstract
Heat shock factor (Hsf1) regulates the expression of molecular chaperones to maintain protein homeostasis. Despite its central role in stress resistance, disease and aging, the mechanisms that control Hsf1 activity remain unresolved. Here we show that in budding yeast, Hsf1 basally associates with the chaperone Hsp70 and this association is transiently disrupted by heat shock, providing the first evidence that a chaperone repressor directly regulates Hsf1 activity. We develop and experimentally validate a mathematical model of Hsf1 activation by heat shock in which unfolded proteins compete with Hsf1 for binding to Hsp70. Surprisingly, we find that Hsf1 phosphorylation, previously thought to be required for activation, in fact only positively tunes Hsf1 and does so without affecting Hsp70 binding. Our work reveals two uncoupled forms of regulation - an ON/OFF chaperone switch and a tunable phosphorylation gain - that allow Hsf1 to flexibly integrate signals from the proteostasis network and cell signaling pathways. DOI: http://dx.doi.org/10.7554/eLife.18638.001Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127643/pdf/Terms of Use
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