Single methyl groups can act as toggle switches to specify transmembrane protein-protein interactions

  1. Li He
  2. Helena Steinocher
  3. Ashish Shelar
  4. Emily B Cohen
  5. Erin N Heim
  6. Birthe B Kragelund
  7. Gevorg Grigoryan
  8. Daniel DiMaio  Is a corresponding author
  1. Yale School of Medicine, United States
  2. University of Copenhagen, Denmark
  3. Dartmouth College, United States

Abstract

Transmembrane domains (TMDs) engage in protein-protein interactions that regulate many cellular processes, but the rules governing the specificity of these interactions are poorly understood. To discover these principles, we analyzed 26-residue model transmembrane proteins consisting exclusively of leucine and isoleucine (called LIL traptamers) that specifically activate the erythropoietin receptor (EPOR) in mouse cells to confer growth factor independence. We discovered that the placement of a single side chain methyl group at specific positions in a traptamer determined whether it associated productively with the TMD of the human EPOR, the mouse EPOR, or both receptors. Association of the traptamers with the EPOR induced EPOR oligomerization in an orientation that stimulated receptor activity. These results highlight the high intrinsic specificity of TMD interactions, demonstrate that a single methyl group can dictate specificity, and define the minimal chemical difference that can modulate the specificity of TMD interactions and the activity of transmembrane proteins.

Article and author information

Author details

  1. Li He

    Department of Genetics, Yale School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Helena Steinocher

    Department of Biology, Structural Biology and NMR Laboratory, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  3. Ashish Shelar

    Department of Genetics, Yale School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Emily B Cohen

    Department of Genetics, Yale School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Erin N Heim

    Department of Genetics, Yale School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Birthe B Kragelund

    Department of Biology, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7454-1761
  7. Gevorg Grigoryan

    Department of Computer Science, Dartmouth College, Hanover, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Daniel DiMaio

    Department of Genetics, Yale School of Medicine, New Haven, United States
    For correspondence
    daniel.dimaio@yale.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2060-5977

Funding

National Institutes of Health (R01 CA037157)

  • Daniel DiMaio

Lundbeckfonden (Lundbeck Foundation)

  • Birthe B Kragelund

Novo Nordisk Foundation (Novo Nordisk Foundation)

  • Birthe B Kragelund

National Institutes of Health (GM113132)

  • Gevorg Grigoryan

National Science Foundation (MCB151032)

  • Gevorg Grigoryan

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

Reviewing Editor

  1. Nir Ben-Tal, Tel Aviv University, Israel

Publication history

  1. Received: April 11, 2017
  2. Accepted: September 1, 2017
  3. Accepted Manuscript published: September 4, 2017 (version 1)
  4. Version of Record published: September 13, 2017 (version 2)

Copyright

© 2017, He 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. Li He
  2. Helena Steinocher
  3. Ashish Shelar
  4. Emily B Cohen
  5. Erin N Heim
  6. Birthe B Kragelund
  7. Gevorg Grigoryan
  8. Daniel DiMaio
(2017)
Single methyl groups can act as toggle switches to specify transmembrane protein-protein interactions
eLife 6:e27701.
https://doi.org/10.7554/eLife.27701

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