Ligand binding induces a conformational change in epidermal growth factor receptor dimers
- Author(s)
- Walker, F; Rothacker, J; Henderson, C; Nice, EC; Catimel, B; Zhang, HH; Scott, AM; Bailey, MF; Orchard, SG; Adams, TE; Liu, ZQ; Garrett, TPJ; Clayton, AHA; Burgess, AW;
- Details
- Publication Year 2012-12,Volume 30,Issue #6,Page 394-409
- Journal Title
- GROWTH FACTORS
- Publication Type
- Journal Article
- Abstract
- 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.
- Publisher
- INFORMA HEALTHCARE
- Keywords
- asymmetric tetramer, aggregation, kinase activation, structural models
- Research Division(s)
- Structural Biology
- Publisher's Version
- https://doi.org/10.3109/08977194.2012.739619
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Creation Date: 2012-12-01 12:00:00