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A structure-based model for ligand binding and dimerization of EGF receptors
Peter Klein1, Dawn Mattoon, Mark A Lemmon
1Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
Summary
Epidermal growth factor receptor (EGFR) activation involves complex binding dynamics. Mathematical modeling reveals that occupied EGFR dimers binding to an external site explains EGF binding patterns in living cells.
Area of Science:
- Biochemistry
- Cell Biology
- Structural Biology
Background:
- Epidermal growth factor receptor (EGFR) activation is crucial for cell signaling.
- Structural studies proposed a mechanism for EGFR autoinhibition and ligand-induced dimerization.
Purpose of the Study:
- To develop a mathematical model for EGF binding and EGFR activation.
- To explain concave-up curvilinear Scatchard plots observed in living cells.
Main Methods:
- Mathematical modeling based on 3D structures of EGFR and ErbB3 extracellular domains.
- Analysis of EGF binding kinetics to intact EGFR in living cells.
Main Results:
- Curvilinear Scatchard plots cannot be explained solely by autoinhibited vs. dimeric EGFR configurations.
- An additional binding event involving occupied EGFR dimers and an external site is required.
- Active EGFR dimers bind EGF 5- to 20-fold more strongly than autoinhibited monomers.
Conclusions:
- The 'external site' may involve interactions with cell membrane components like coated pits.
- High-affinity EGF-binding sites in intact cells do not directly correspond to the active extended EGFR configuration.