Abstract
Eph receptors are the largest family of receptor tyrosine kinases and by interactions with ephrin ligands mediate a myriad of processes from embryonic development to adult tissue homeostasis. The interaction of Eph receptors, especially at their transmembrane (TM) domains is key to understanding their mechanism of signal transduction across cellular membranes. We review the structural and functional aspects of EphA1/A2 association and the techniques used to investigate their TM domains: NMR, molecular modelling/dynamics simulations and fluorescence. We also introduce transmembrane peptides, which can be used to alter Eph receptor signaling and we provide a perspective for future studies.
Highlights
Several in silico approaches have been shown to provide a reasonably quick and efficient tool for assessment of the mode of transmembrane domain (TMD) association in membranes, especially when direct experimental techniques fail or are highly resource consuming. These in silico approaches can be subdivided into two major categories: ab initio molecular prediction based on sequence or packing features and molecular modelling integrated with molecular dynamics simulations
We are still in the process of understanding the structural components involved in Erythropoietin-producing hepatocellular carcinoma receptors (Ephs) receptor dimerization/oligomerization and Eph-ephrin interaction, possibly in cis [77] as well as in trans, all features which contribute to, if not comprise the regulatory mechanism of Eph receptor signaling
From the reported results it is clear that the TMD has a significant role to play in signal transduction across the plasma membrane
Summary
The traditional workhorse of structural biology, x-ray crystallography, has generally experienced problems with the crystallization of single-pass membrane proteins and only relatively recently have TMD structures been obtained using crystallization in the cubic lipid phase [29], which can lead to non-physiological structures. The N-terminus of the transmembrane helix is stabilized by the carboxyl group of Glu547, whereas its deprotonation results in a fractional unfolding of the helix, and rearrangement of hydrogen bonds and of helix-helix packing [22] This indicates that local perturbations such as pH changes and membrane lipid composition could alter TMD structural dynamics and could regulate EphA1 conformational flexibility and activation. Compared with the right-handed TM dimer of EphA1, the EphA2 TM dimer shows the left-handed arrangement of TM helices embedded into lipid bicelles, evidence that TM domains of the Eph receptors can self-associate in different configurations This points to the diversity in the formation of TMDs within a family of RTKs and is evidence for the rotation coupled mechanism of activation of these receptors [39,40]. Let us look in more detail at the dimerization motifs in the TMD
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