Understanding the Structural Basis of Epha2‐dimerization, ‐membrane Interactions and Its Implications in Cancer Progression

Abstract

EphA2 plays a critical role in cellular growth, differentiation and motility. In line with EphA2 mRNA expression in multiple tissues and organs, its overexpression is reported in several different cancer types, and even in cancer-derived cell lines. EphA2 overexpression may have significance and could be used as a biomarker in the clinical management of cancer. Besides this, the differential EphA2 expression in normal versus cancer cells makes it a key therapeutic target. In EphA2, ligand binding regulates the monomer-dimer equilibrium through stabilization of the dimeric state by inducing a conformational change in the extracellular domain. Thus, dimerization is a key regulatory step in the activity and signaling process of EphA2. In EphA2, the juxtamembrane (JM) region follows the TM domain at one end and connects to a catalytic domain at the other. The JM domain functions in synergy with the TM domain for signal transduction. The JM domain has several basic residues (K/R) that are closely positioned to the membrane surface. Other signaling molecules specifically PIP2 and PIP3 utilize these basic amino acids for binding and occlude the nearby region from phosphorylation. Therefore, studying the structural mechanism of EphA2 dimerization and membrane interactions will help us better understand the activity and signaling of this receptor in different cancer types. Importantly, working with membrane proteins is extremely challenging. However, the recent developments in molecular dynamics simulation have provided a powerful tool to study membrane proteins and their interactions. Here, we modeled the relevant domains of the EphA2 receptor and studying its structural mechanism of activation for signaling by harnessing the power of advanced in-silico techniques. Our objective is to understand the structural basis of EphA2 dimerization and the role of the transmembrane region in signal transduction of EphA2 and also the characterization of protein-lipid bilayer interaction and their role in EphA2 regulation.