PUBLICATION
Membrane interaction of bound ligands contributes to the negative binding cooperativity of the EGF receptor
- Authors
- Arkhipov, A., Shan, Y., Kim, E.T., Shaw, D.E.
- ID
- ZDB-PUB-170214-308
- Date
- 2014
- Source
- PLoS Computational Biology 10: e1003742 (Journal)
- Registered Authors
- Keywords
- Dimers (Chemical physics), Free energy, Biochemical simulations, Cell membranes, Membrane receptor signaling, Crystal structure, Glycosylation, Simulation and modeling
- MeSH Terms
-
- Animals
- Binding Sites
- Cell Membrane/chemistry*
- Chickens
- Computational Biology
- Ligands
- Mammals
- Molecular Dynamics Simulation
- Protein Binding*
- Protein Conformation
- Protein Structure, Tertiary*
- Zebrafish
- PubMed
- 25058506 Full text @ PLoS Comput. Biol.
Citation
Arkhipov, A., Shan, Y., Kim, E.T., Shaw, D.E. (2014) Membrane interaction of bound ligands contributes to the negative binding cooperativity of the EGF receptor. PLoS Computational Biology. 10:e1003742.
Abstract
The epidermal growth factor receptor (EGFR) plays a key role in regulating cell proliferation, migration, and differentiation, and aberrant EGFR signaling is implicated in a variety of cancers. EGFR signaling is triggered by extracellular ligand binding, which promotes EGFR dimerization and activation. Ligand-binding measurements are consistent with a negatively cooperative model in which the ligand-binding affinity at either binding site in an EGFR dimer is weaker when the other site is occupied by a ligand. This cooperativity is widely believed to be central to the effects of ligand concentration on EGFR-mediated intracellular signaling. Although the extracellular portion of the human EGFR dimer has been resolved crystallographically, the crystal structures do not reveal the structural origin of this negative cooperativity, which has remained unclear. Here we report the results of molecular dynamics simulations suggesting that asymmetrical interactions of the two binding sites with the membrane may be responsible (perhaps along with other factors) for this negative cooperativity. In particular, in our simulations the extracellular domains of an EGFR dimer spontaneously lay down on the membrane in an orientation in which favorable membrane contacts were made with one of the bound ligands, but could not be made with the other. Similar interactions were observed when EGFR was glycosylated, as it is in vivo.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping