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Full Record Details
Persistent URL
http://purl.org/net/epubs/work/55973
Record Status
Checked
Record Id
55973
Title
Human-EGFR aligned on the plasma membrane adopts key features of Drosophila-EGFR asymmetry
Contributors
CJ Tynan (STFC Rutherford Appleton Lab.)
,
SK Roberts (STFC Daresbury Lab.)
,
DJ Rolfe (STFC Rutherford Appleton Lab.)
,
DT Clarke (STFC Rutherford Appleton Lab.)
,
HH Loeffler (STFC Daresbury Lab.)
,
J Kaestner (Stuttgart U.)
,
MD Winn (STFC Daresbury Lab.)
,
PJ Parker (KCL)
,
ML Martin-Fernandez (STFC Rutherford Appleton Lab.)
Abstract
The ability of epidermal growth factor receptor (EGFR) to control cell fate is defined by its affinity for ligand. Current models suggest that ligand-binding heterogeneity arises from negative cooperativity in signaling receptor dimers, for which the asymmetry of the extracellular region of the Drosophila EGFR has recently provided a structural basis. However, no asymmetry is apparent in the isolated extracellular region of the human EGFR. Human EGFR also differs from the Drosophila EGFR in that negative cooperativity is found only in full-length receptors in cells. To gain structural insights into the human EGFR in situ, we developed an approach based on quantitative Förster resonance energy transfer (FRET) imaging, combined with Monte Carlo and molecular dynamics simulations, to probe receptor conformation in epithelial cells. We experimentally demonstrate a high-affinity ligand-binding human EGFR conformation consistent with the extracellular region aligned flat on the plasma membrane. We explored the relevance of this conformation to ligand-binding heterogeneity and found that the asymmetry of this structure shares key features with that of the Drosophila EGFR, suggesting that the structural basis for negative cooperativity is conserved from invertebrates to humans but that in human EGFR the extracellular region asymmetry requires interactions with the plasma membrane.
Organisation
CLF
,
CSE
,
CLF-LFS
,
CSE-BIO
,
STFC
Keywords
Biology
Funding Information
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Licence Information:
Language
English (EN)
Type
Details
URI(s)
Local file(s)
Year
Journal Article
Mol Cell Biol
31, no. 11 (2011): 2241-2252.
doi:10.1128/MCB.01431-10
2011
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