Multivalency regulates activity in an intrinsically disordered transcription factor

  1. Sarah A Clark
  2. Janette B Myers
  3. Ashleigh King
  4. Radovan Fiala
  5. Jiri Novacek
  6. F. Grant Pearce
  7. Jörg Heierhorst
  8. Steve L Reichow
  9. Elisar J Barbar  Is a corresponding author
  1. Oregon State University, United States
  2. Portland State University, United States
  3. St. Vincent's Institute of Medical Research, Australia
  4. Masaryk University, Czech Republic
  5. University of Canterbury, New Zealand

Abstract

The transcription factor ASCIZ (ATMIN, ZNF822) has an unusually high number of recognition motifs for the product of its main target gene, the hub protein LC8 (DYNLL1). Using a combination of biophysical methods, structural analysis by NMR and electron microscopy, and cellular transcription assays, we developed a model that proposes a concerted role of intrinsic disorder and multiple LC8 binding events in regulating LC8 transcription. We demonstrate that the long intrinsically disordered C-terminal domain of ASCIZ binds LC8 to form a dynamic ensemble of complexes with a gradient of transcriptional activity that is inversely proportional to LC8 occupancy. The preference for low occupancy complexes at saturating LC8 concentrations with both human and Drosophila ASCIZ indicates that negative cooperativity is an important feature of ASCIZ-LC8 interactions. The prevalence of intrinsic disorder and multivalency among transcription factors suggests that formation of heterogeneous, dynamic complexes is a widespread mechanism for tuning transcriptional regulation.

Data availability

The chemical shifts for dLBD ASCIZ have been deposited in the Biological Magnetic Resonance Data Bank under accession code 27412 (http://www.bmrb.wisc.edu/data_library/summary/index.php?bmrbId=27412).

The following data sets were generated

Article and author information

Author details

  1. Sarah A Clark

    Department of Biochemistry and Biophysics, Oregon State University, Corvallis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Janette B Myers

    Department of Chemistry, Portland State University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7758-2649
  3. Ashleigh King

    St. Vincent's Institute of Medical Research, Fitzroy, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. Radovan Fiala

    Central European Institute of Technology, Masaryk University, Brno, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
  5. Jiri Novacek

    Central European Institute of Technology, Masaryk University, Brno, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
  6. F. Grant Pearce

    School of Biological Sciences, University of Canterbury, Christchurch, New Zealand
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2683-0331
  7. Jörg Heierhorst

    St. Vincent's Institute of Medical Research, Fitzroy, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2789-9514
  8. Steve L Reichow

    Department of Chemistry, Portland State University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Elisar J Barbar

    Department of Biochemistry and Biophysics, Oregon State University, Corvallis, United States
    For correspondence
    barbare@oregonstate.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4892-5259

Funding

National Institute of General Medical Sciences (R01-084276)

  • Elisar J Barbar

National Health and Medical Research Council (APP1026125)

  • Jörg Heierhorst

National Institute of General Medical Sciences (R35GM124779)

  • Steve L Reichow

National Institutes of Health (1S10OD018518)

  • Elisar J Barbar

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Lewis E Kay, University of Toronto, Canada

Publication history

  1. Received: February 28, 2018
  2. Accepted: April 23, 2018
  3. Accepted Manuscript published: May 1, 2018 (version 1)
  4. Version of Record published: May 22, 2018 (version 2)
  5. Version of Record updated: August 3, 2018 (version 3)

Copyright

© 2018, Clark 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. Sarah A Clark
  2. Janette B Myers
  3. Ashleigh King
  4. Radovan Fiala
  5. Jiri Novacek
  6. F. Grant Pearce
  7. Jörg Heierhorst
  8. Steve L Reichow
  9. Elisar J Barbar
(2018)
Multivalency regulates activity in an intrinsically disordered transcription factor
eLife 7:e36258.
https://doi.org/10.7554/eLife.36258
  1. Further reading

Further reading

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