Membrane Interaction of Bound Ligands Contributes to the Negative Binding Cooperativity of the EGF Receptor

Anton Arkhipov, Yibing Shan, Eric T Kim and David E Shaw

PLOS Computational Biology, 2014, vol. 10, issue 7, 1-11

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.Author Summary: Epidermal growth factor receptor (EGFR) molecules are of central importance in cellular communication. Embedded in the cell membrane, these receptors bind epidermal growth factor (EGF) molecules outside the cell and translate this binding into specific biochemical signals inside the cell, which in turn trigger cell proliferation, migration, or differentiation. EGFR dysfunction has been implicated in a variety of cancers, and EGFR-targeting drugs are commonly used in cancer treatments. It has been widely assumed that the extracellular portion of an EGFR molecule protrudes perpendicularly from the cell membrane. In detailed, atomic-level computer simulations, however, we find that it lies down on the membrane, placing its EGF-binding site adjacent to the membrane surface. We further show that EGF may interact with EGFR in two distinct ways (with or without the involvement of the membrane). This may explain the experimental finding that an EGF molecule binds to EGFR more weakly at higher EGF concentration. This phenomenon, which is a manifestation of an underlying negative cooperativity, is an important but poorly understood characteristic of EGFR activity. In this study, we also model and analyze the glycan chains attached to EGFR, which are integral to its behavior in living cells.

Date: 2014
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1003742

DOI: 10.1371/journal.pcbi.1003742

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