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Intrinsically disordered linkers determine the interplay between phase separation and gelation in multivalent proteins

  1. Tyler S Harmon
  2. Alex S Holehouse
  3. Michael K Rosen
  4. Rohit V Pappu  Is a corresponding author
  1. Washington University in St. Louis, United States
  2. University of Texas Southwestern Medical Center, United States
Research Article
  • Cited 77
  • Views 4,611
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Cite this article as: eLife 2017;6:e30294 doi: 10.7554/eLife.30294

Abstract

Phase transitions of linear multivalent proteins control the reversible formation of many intracellular membraneless bodies. Specific non-covalent crosslinks involving domains / motifs lead to system-spanning networks referred to as gels. Gelation transitions can occur with or without phase separation. In gelation driven by phase separation multivalent proteins and their ligands condense into dense droplets, and gels form within droplets. System spanning networks can also form without a condensation or demixing of proteins into droplets. Gelation driven by phase separation requires lower protein concentrations, and seems to be the biologically preferred mechanism for forming membraneless bodies. Here, we use coarse-grained computer simulations and the theory of associative polymers to uncover the physical properties of intrinsically disordered linkers that determine the extent to which gelation of linear multivalent proteins is driven by phase separation. Our findings are relevant for understanding how sequence-encoded information in disordered linkers influences phase transitions of multivalent proteins.

Article and author information

Author details

  1. Tyler S Harmon

    Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Alex S Holehouse

    Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4155-5729
  3. Michael K Rosen

    Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0775-7917
  4. Rohit V Pappu

    Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, United States
    For correspondence
    pappu@wustl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2568-1378

Funding

National Institutes of Health (RO1-GM56322)

  • Michael K Rosen

National Science Foundation (MCB1614766)

  • Rohit V Pappu

Howard Hughes Medical Institute

  • Michael K Rosen

St. Jude Children's Research Hospital

  • Rohit V Pappu

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

Reviewing Editor

  1. Anthony A Hyman, Max Planck Institute of Molecular Cell Biology and Genetics, Germany

Publication history

  1. Received: July 9, 2017
  2. Accepted: October 29, 2017
  3. Accepted Manuscript published: November 1, 2017 (version 1)
  4. Version of Record published: November 27, 2017 (version 2)

Copyright

© 2017, Harmon 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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