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Cell Rep. 2014 Nov 20;9(4):1306-17. doi: 10.1016/j.celrep.2014.10.010. Epub 2014 Nov 6.

Complex relationship between ligand binding and dimerization in the epidermal growth factor receptor.

Author information

1
Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
2
Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
3
Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: mlemmon@mail.med.upenn.edu.

Abstract

The epidermal growth factor receptor (EGFR) plays pivotal roles in development and is mutated or overexpressed in several cancers. Despite recent advances, the complex allosteric regulation of EGFR remains incompletely understood. Through efforts to understand why the negative cooperativity observed for intact EGFR is lost in studies of its isolated extracellular region (ECR), we uncovered unexpected relationships between ligand binding and receptor dimerization. The two processes appear to compete. Surprisingly, dimerization does not enhance ligand binding (although ligand binding promotes dimerization). We further show that simply forcing EGFR ECRs into preformed dimers without ligand yields ill-defined, heterogeneous structures. Finally, we demonstrate that extracellular EGFR-activating mutations in glioblastoma enhance ligand-binding affinity without directly promoting EGFR dimerization, suggesting that these oncogenic mutations alter the allosteric linkage between dimerization and ligand binding. Our findings have important implications for understanding how EGFR and its relatives are activated by specific ligands and pathological mutations.

PMID:
25453753
PMCID:
PMC4254573
DOI:
10.1016/j.celrep.2014.10.010
[Indexed for MEDLINE]
Free PMC Article

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