Paper Info
Title
Membrane Interaction Of Bound Ligands Contributes To The Negative Binding Cooperativity Of The Egf Receptor
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.
Year
DOI
Venue
2014
10.1371/journal.pcbi.1003742
PLOS COMPUTATIONAL BIOLOGY
Field
DocType
Volume
Plasma protein binding,Cooperativity,Binding site,ERBB3,Biology,Cooperative binding,Ligand (biochemistry),Cell biology,Cell membrane,Epidermal growth factor receptor
Journal
10
Issue
ISSN
Citations 
7
1553-7358
0
PageRank 
References 
Authors
0.34
4
4
Name
Order
Citations
PageRank
Anton Arkhipov100.68
Yibing Shan200.34
Eric T Kim300.34
David Elliot Shaw4890139.33