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Structural basis for negative cooperativity in growth factor binding to an EGF receptor.

Alvarado D, Klein DE, Lemmon MA
Cell 142 568-79 (2010)
Cited: 116 times
EuropePMC logo PMID: 20723758

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.

Reviews - 3ltg mentioned but not cited (3)

  1. The EGFR family: not so prototypical receptor tyrosine kinases. Lemmon MA, Schlessinger J, Ferguson KM. Cold Spring Harb Perspect Biol 6 a020768 (2014)
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Articles - 3ltg mentioned but not cited (6)

  1. Structural basis for negative cooperativity in growth factor binding to an EGF receptor. Alvarado D, Klein DE, Lemmon MA. Cell 142 568-579 (2010)
  2. Human epidermal growth factor receptor (EGFR) aligned on the plasma membrane adopts key features of Drosophila EGFR asymmetry. Tynan CJ, Roberts SK, Rolfe DJ, Clarke DT, Loeffler HH, Kästner J, Winn MD, Parker PJ, Martin-Fernandez ML. Mol Cell Biol 31 2241-2252 (2011)
  3. Structures of the HER2-HER3-NRG1β complex reveal a dynamic dimer interface. Diwanji D, Trenker R, Thaker TM, Wang F, Agard DA, Verba KA, Jura N. Nature 600 339-343 (2021)
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  5. Molecular dynamics simulations of transitions for ECD epidermal growth factor receptors show key differences between human and drosophila forms of the receptors. Perilla JR, Leahy DJ, Woolf TB. Proteins 81 1113-1126 (2013)
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Reviews citing this publication (24)

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Articles citing this publication (83)

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