1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics

Molecular basis for multimerization in the activation of the epidermal growth factor receptor

  1. Yongjian Huang
  2. Shashank Bharill
  3. Deepti Karandur
  4. Sean M Peterson
  5. Morgan Marita
  6. Xiaojun Shi
  7. Megan J Kaliszewski
  8. Adam W Smith
  9. Ehud Y Isacoff
  10. John Kuriyan  Is a corresponding author
  1. University of California, Berkeley, United States
  2. University of Akron, United States
https://doi.org/10.7554/eLife.14107
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  1. Yongjian Huang
  2. Shashank Bharill
  3. Deepti Karandur
  4. Sean M Peterson
  5. Morgan Marita
  6. Xiaojun Shi
  7. Megan J Kaliszewski
  8. Adam W Smith
  9. Ehud Y Isacoff
  10. John Kuriyan
(2016)
Molecular basis for multimerization in the activation of the epidermal growth factor receptor
eLife 5:e14107.
https://doi.org/10.7554/eLife.14107
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  3. Download .RIS

Abstract

The epidermal growth factor receptor (EGFR) is activated by dimerization, but activation also generates higher-order multimers, whose nature and function are poorly understood. We have characterized ligand-induced dimerization and multimerization of EGFR using single-molecule analysis, and show that multimerization can be blocked by mutations in a specific region of Domain IV of the extracellular module. These mutations reduce autophosphorylation of the C-terminal tail of EGFR and attenuate phosphorylation of phosphatidyl inositol 3-kinase, which is recruited by EGFR. The catalytic activity of EGFR is switched on through allosteric activation of one kinase domain by another, and we show that if this is restricted to dimers, then sites in the tail that are proximal to the kinase domain are phosphorylated in only one subunit. We propose a structural model for EGFR multimerization through self-association of ligand-bound dimers, in which the majority of kinase domains are activated cooperatively, thereby boosting tail phosphorylation.

Article and author information

Author details

  1. Yongjian Huang

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.

  2. Shashank Bharill

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.

  3. Deepti Karandur

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.

  4. Sean M Peterson

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.

  5. Morgan Marita

    Department of Chemistry, University of Akron, Akron, United States
    Competing interests
    No competing interests declared.

  6. Xiaojun Shi

    Department of Chemistry, University of Akron, Akron, United States
    Competing interests
    No competing interests declared.

  7. Megan J Kaliszewski

    Department of Chemistry, University of Akron, Akron, United States
    Competing interests
    No competing interests declared.

  8. Adam W Smith

    Department of Chemistry, University of Akron, Akron, United States
    Competing interests
    No competing interests declared.

  9. Ehud Y Isacoff

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.

  10. John Kuriyan

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    For correspondence
    jkuriyan@mac.com
    Competing interests
    John Kuriyan, Senior editor, eLife.

Reviewing Editor

  1. Volker Dötsch, Goethe University, Germany

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Our Xenopus protocol has been approved by Institutional Animal Care and Use Committee (IACUC) of the University of California.

Version history

  1. Received: December 29, 2015
  2. Accepted: March 27, 2016
  3. Accepted Manuscript published: March 28, 2016 (version 1)
  4. Accepted Manuscript updated: March 30, 2016 (version 2)
  5. Version of Record published: June 10, 2016 (version 3)

Copyright

© 2016, Huang 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. Yongjian Huang
  2. Shashank Bharill
  3. Deepti Karandur
  4. Sean M Peterson
  5. Morgan Marita
  6. Xiaojun Shi
  7. Megan J Kaliszewski
  8. Adam W Smith
  9. Ehud Y Isacoff
  10. John Kuriyan
(2016)
Molecular basis for multimerization in the activation of the epidermal growth factor receptor
eLife 5:e14107.
https://doi.org/10.7554/eLife.14107

Share this article

https://doi.org/10.7554/eLife.14107

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