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

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  • Yongjian Huang
    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
  • Shashank Bharill
    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
  • Deepti Karandur
    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
  • Sean M Peterson
    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
  • Morgan Marita
    Department of Chemistry, University of Akron, Akron, United States
  • Xiaojun Shi
    Department of Chemistry, University of Akron, Akron, United States
  • Megan J Kaliszewski
    Department of Chemistry, University of Akron, Akron, United States
  • Adam W Smith
    Department of Chemistry, University of Akron, Akron, United States
  • Ehud Y Isacoff
    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
  • John Kuriyan
    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Description

<jats:p>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.</jats:p>

Journal

  • eLife

    eLife 5 e14107-, 2016-03-28

    eLife Sciences Publications, Ltd

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