Abstract
SummaryEphs are transmembrane receptors that mediate cell-cell signaling. The N-terminal ectodomain binds ligands and enables receptor clustering, which activates the intracellular kinase. Relatively little is known about the function of the membrane-proximal fibronectin domain 2 (FN2) of the ectodomain. Multiscale molecular dynamics simulations reveal that FN2 interacts with lipid bilayers via a site comprising K441, R443, R465, Q462, S464, S491, W467, F490, and P459–461. FN2 preferentially binds anionic lipids, a preference that is reduced in the mutant K441E + R443E. We confirm these results by measuring the binding of wild-type and mutant FN2 domains to lipid vesicles. In simulations of the complete EphA2 ectodomain plus the transmembrane region, we show that FN2 anchors the otherwise flexible ectodomain at the surface of the bilayer. Altogether, our data suggest that FN2 serves a dual function of interacting with anionic lipids and constraining the structure of the EphA2 ectodomain to adopt membrane-proximal configurations.
Highlights
The ephrin receptors (Ephs) are the largest group within the family of receptor tyrosine kinases (RTKs)
The ectodomain is made up of a ligand-binding domain (LBD), which interacts with ephrin ligands, a Sushi domain, an epidermal growth factor-like (EGF) domain, and two fibronectin type III domains (FN1 and fibronectin domain 2 (FN2))
Recent crystal structures of the entire ectodomains of two Eph receptors, EphA2 and EphA4, in complex with and without ephrin ligands, have revealed that ligand-induced Eph clustering is driven to a large extent by the N-terminal LBD and Sushi domains (Himanen et al, 2010; Seiradake et al, 2010, 2013; Xu et al, 2013)
Summary
Chavent et al combine multiscale molecular dynamics simulations with a biochemical assay to describe the interactions of the EphA2 receptor FN2 domain with the anionic lipids of a model membrane. This provides insights into the dynamic behavior of the receptor at the cell surface.
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