Ligand binding induces a conformational change in epidermal growth factor receptor dimers

Francesca Walker, Julie Rothacker, Christine Henderson, Edouard Nice, Bruno Catimel, Hui-Hua Zhang, Andrew M Scott, Michael F Bailey, Suzanne Gaye Orchard, Timothy E Adams, Zhangqi QI Liu, Thomas PJ Garrett, Andrew H A Clayton, Anthony W Burgess

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19 Citations (Scopus)


The activation of the epidermal growth factor receptor (EGFR) kinase requires ligand binding to the extracellular domain (ECD). Previous reports demonstrate that the EGFR-ECD can be crystallized in two conformations - a tethered monomer or, in the presence of ligand, an untethered back-to-back dimer. We use Biosensor analysis to demonstrate that even in the monomeric state different C-terminal extensions of both truncated (EGFR(1-501))-ECD and full-length EGFR(1-621)-ECD can change the conformation of the ligand-binding site. The binding of a monoclonal antibody mAb806, which recognizes the dimer interface, to the truncated EGFR(1-501)-Fc fusion protein is reduced in the presence of ligand, consistent with a change in conformation. On the cell surface, the presence of erythroblastosis B2 (erbB2) increases the binding of mAb806 to the EGFR. The conformation of the erbB2: EGFR heterodimer interface changes when the cells are treated with epidermal growth factor (EGF). We propose that ligand induces kinase-inactive, pre-formed EGFR dimers and heterodimers to change conformation leading to kinase-active tetramers, where kinase activation occurs via an asymmetric interaction between EGFR dimers.
Original languageEnglish
Pages (from-to)394 - 409
Number of pages16
JournalGrowth Factors
Issue number6
Publication statusPublished - 2012
Externally publishedYes

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