Genetically tunable frustration controls allostery in an intrinsically disordered transcription factor

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.

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Author details

  1. Jing Li

    T.C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jordan T White

    Department of Biology, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3202-4181
  3. Harry Saavedra

    T.C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. James O Wrabl

    T.C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Hesam N Motlagh

    T.C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Kaixian Liu

    Department of Biology, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. James Sowers

    Department of Biology, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Trina Schroer

    Department of Biology, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5065-1835
  9. E Brad Thompson

    Department of Biology, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1578-0241
  10. Vincent J Hilser

    T.C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, United States
    For correspondence
    hilser@jhu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7173-0073

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

  1. John Kuriyan, University of California, Berkeley, United States

Publication history

  1. Received: July 24, 2017
  2. Accepted: October 11, 2017
  3. Accepted Manuscript published: October 12, 2017 (version 1)
  4. Version of Record published: November 21, 2017 (version 2)
  5. 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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  1. Jing Li
  2. Jordan T White
  3. Harry Saavedra
  4. James O Wrabl
  5. Hesam N Motlagh
  6. Kaixian Liu
  7. James Sowers
  8. Trina Schroer
  9. E Brad Thompson
  10. Vincent J Hilser
(2017)
Genetically tunable frustration controls allostery in an intrinsically disordered transcription factor
eLife 6:e30688.
https://doi.org/10.7554/eLife.30688

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