Epidermal growth factor receptor dimerization and activation require ligand-induced conformational changes in the
Jessica P Dawson1, Mitchell B Berger, Chun-Chi Lin
1Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, 19104-6059, USA.
Molecular and Cellular Biology
|August 19, 2005
Summary
Epidermal growth factor receptor (EGFR) dimerization requires more than just exposing a key arm. Specific intramolecular interactions in domain II are crucial for stabilizing EGFR dimers and may influence ErbB receptor family specificity.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Ligand binding induces epidermal growth factor receptor (EGFR) dimerization through domain rearrangements.
- Exposing the dimerization arm alone is insufficient for stable receptor dimerization, indicating additional contacts are necessary.
Purpose of the Study:
- To precisely map the contributions of various contacts to the EGFR dimer interface.
- To understand the role of ligand-induced conformational changes in stabilizing EGFR dimers.
Main Methods:
- Site-directed mutagenesis of potential dimer interface contacts.
- Analysis of receptor dimerization, activation, and ligand binding.
- Crystallographic studies to guide mutation targets.
Main Results:
- Domain II provides over 90% of the dimerization energy for the extracellular region; domain IV contributes minimally.
- A loop C-terminal to the dimerization arm in domain II critically contributes to dimer stability.
- Ligand-induced intramolecular interactions in domain II stabilize the dimer interface.
Conclusions:
- EGFR dimerization is stabilized by a critical loop in domain II and ligand-induced intramolecular interactions, not solely the dimerization arm.
- These findings provide insights into the mechanism of EGFR activation and may explain ErbB receptor homo- and heterodimerization specificity.
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