Genetically tunable frustration controls allostery in an intrinsically disordered transcription factor
- Johns Hopkins University, United States
Abstract
Intrinsically disordered proteins (IDPs) present a functional paradox because they lack stable tertiary structure, but nonetheless play a central role in signaling, utilizing a process known as allostery. Historically, allostery in structured proteins has been interpreted in terms of propagated structural changes that are induced by effector binding. Thus, it is not clear how IDPs, lacking such well-defined structures, can allosterically affect function. Here we show a mechanism by which an IDP can allosterically control function by simultaneously tuning transcriptional activation and repression, using a novel strategy that relies on the principle of 'energetic frustration'. We demonstrate that human glucocorticoid receptor tunes this signaling in vivo by producing translational isoforms differing only in the length of the disordered region, which modulates the degree of frustration. We expect this frustration-based model of allostery will prove to be generally important in explaining signaling in other IDPs.
Article and author information
Author details
Funding
National Science Foundation (MCB-1330211)
- Jing Li
- Jordan T White
- Harry Saavedra
- James O Wrabl
- Hesam N Motlagh
- Kaixian Liu
- James Sowers
- Vincent J Hilser
Johns Hopkins University (JHU Institutional Funds)
- Vincent J Hilser
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- John Kuriyan, University of California, Berkeley, United States
Version history
- Received: July 24, 2017
- Accepted: October 11, 2017
- Accepted Manuscript published: October 12, 2017 (version 1)
- Version of Record published: November 21, 2017 (version 2)
- Version of Record updated: February 12, 2018 (version 3)
Copyright
© 2017, Li et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Genetically tunable frustration controls allostery in an intrinsically disordered transcription factor
eLife 6:e30688.
https://doi.org/10.7554/eLife.30688
Further reading
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- Biochemistry and Chemical Biology
- Structural Biology and Molecular Biophysics
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