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

Abstract

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.

Authors:
; ;  [1]
  1. UPENN-MED
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1002694
Resource Type:
Journal Article
Journal Name:
Cell
Additional Journal Information:
Journal Volume: 142; Journal Issue: (4) ; 08, 2010; Journal ID: ISSN 0092-8674
Country of Publication:
United States
Language:
ENGLISH
Subject:
36 MATERIALS SCIENCE; AFFINITY; CRYSTAL STRUCTURE; DIMERIZATION; DIMERS; DROSOPHILA; GROWTH FACTORS; PHOSPHOTRANSFERASES; REGULATIONS; TYROSINE

Citation Formats

Alvarado, Diego, Klein, Daryl E, and Lemmon, Mark A. Structural Basis for Negative Cooperativity in Growth Factor Binding to an EGF Receptor. United States: N. p., 2010. Web. doi:10.1016/j.cell.2010.07.015.
Alvarado, Diego, Klein, Daryl E, & Lemmon, Mark A. Structural Basis for Negative Cooperativity in Growth Factor Binding to an EGF Receptor. United States. https://doi.org/10.1016/j.cell.2010.07.015
Alvarado, Diego, Klein, Daryl E, and Lemmon, Mark A. 2010. "Structural Basis for Negative Cooperativity in Growth Factor Binding to an EGF Receptor". United States. https://doi.org/10.1016/j.cell.2010.07.015.
@article{osti_1002694,
title = {Structural Basis for Negative Cooperativity in Growth Factor Binding to an EGF Receptor},
author = {Alvarado, Diego and Klein, Daryl E and Lemmon, Mark A},
abstractNote = {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.},
doi = {10.1016/j.cell.2010.07.015},
url = {https://www.osti.gov/biblio/1002694}, journal = {Cell},
issn = {0092-8674},
number = (4) ; 08, 2010,
volume = 142,
place = {United States},
year = {Mon Sep 27 00:00:00 EDT 2010},
month = {Mon Sep 27 00:00:00 EDT 2010}
}