Molecular basis for multimerization in the activation of the epidermal growth factor receptor
Yongjian Huang,
Shashank Bharill,
Deepti Karandur,
Sean M Peterson,
Morgan Marita,
Xiaojun Shi,
Megan J Kaliszewski,
Adam W Smith,
Ehud Y Isacoff,
John Kuriyan
Affiliations
Yongjian Huang
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States; Biophysics Graduate Group, 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; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States
Sean M Peterson
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States; Howard Hughes Medical Institute, 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
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States; Biophysics Graduate Group, University of California, Berkeley, Berkeley, United States; Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, United States; Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, United States
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States; Biophysics Graduate Group, University of California, Berkeley, Berkeley, United States; Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, United States; Department of Chemistry, University of California, Berkeley, Berkeley, United States
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.
