Structural Basis for Negative Cooperativity in Growth Factor Binding to an EGF Receptor

Journal Article · Mon Sep 27 04:00:00 EDT 2010 · Cell

DOI:https://doi.org/10.1016/j.cell.2010.07.015· OSTI ID:1002694

Alvarado, Diego; Klein, Daryl E; Lemmon, Mark A ^[1]

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1. UPENN-MED

Transmembrane signaling by the epidermal growth factor receptor (EGFR) involves ligand-induced dimerization and allosteric regulation of the intracellular tyrosine kinase domain. Crystallographic studies have shown how ligand binding induces dimerization of the EGFR extracellular region but cannot explain the high-affinity and low-affinity classes of cell-surface EGF-binding sites inferred from curved Scatchard plots. From a series of crystal structures of the Drosophila EGFR extracellular region, we show here how Scatchard plot curvature arises from negatively cooperative ligand binding. The first ligand-binding event induces formation of an asymmetric dimer with only one bound ligand. The unoccupied site in this dimer is structurally restrained, leading to reduced affinity for binding of the second ligand, and thus negative cooperativity. Our results explain the cell-surface binding characteristics of EGF receptors and suggest how individual EGFR ligands might stabilize distinct dimeric species with different signaling properties.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1002694
• Journal Information: Cell, Journal Name: Cell Journal Issue: (4) ; 08, 2010 Vol. 142; ISSN 0092-8674; ISSN CELLB5
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

36 MATERIALS SCIENCE
AFFINITY
CRYSTAL STRUCTURE
DIMERIZATION
DIMERS
DROSOPHILA
GROWTH FACTORS
PHOSPHOTRANSFERASES
REGULATIONS
TYROSINE