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Cholesterol-dependent dimerization and conformational dynamics of EphA2 receptors from coarse-grained and all-atom
Amita Rani Sahoo1, Nisha Bhattarai1, Matthias Buck2
1Departments of Physiology and Biophysics, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
Abstract:
The EphA2 transmembrane receptor regulates cellular growth, differentiation, and motility, and its overexpression in various cancers makes it a potential biomarker for clinical cancer management. EphA2 signaling occurs through ligand-induced dimerization where the transmembrane (TM) and juxtamembrane (JM) domains play crucial roles in stabilizing the dimer conformations, thereby facilitating signal transduction. Electrostatic interactions between basic JM residues and signaling lipids (PIP2 and PIP3) regulate phosphorylation while cholesterol's potential role in modulating EphA2 activation remains unclear. To investigate this, we modeled the TM-full JM peptide of EphA2 and employed coarse-grain and all-atom simulations to investigate its dimerization in cholesterol-rich and cholesterol-deficient membranes. Our findings reveal that cholesterol stabilizes specific TM dimers and TM-JM interactions with PIP2, highlighting the importance of membrane composition in EphA2 dimerization, oligomerization, and clustering. These insights enhance our understanding of lipid-mediated regulation of EphA2 and its implications in receptor signaling and cancer progression.
Insights
Cholesterol stabilizes EphA2 receptor dimerization by interacting with its transmembrane and juxtamembrane domains. This finding clarifies lipid regulation of EphA2 signaling, crucial for understanding cancer progression.
Area of Science:
- Molecular Biology
- Biophysics
- Cancer Research
Background:
- The EphA2 receptor tyrosine kinase is implicated in cancer progression due to its role in cell growth, differentiation, and motility.
- EphA2 signaling is initiated by ligand-induced dimerization, involving its transmembrane (TM) and juxtamembrane (JM) domains.
- Lipid interactions, particularly with PIP2 and PIP3, are known to regulate EphA2 phosphorylation, but cholesterol's role is undefined.
Purpose of the Study:
- To investigate the role of cholesterol in modulating EphA2 receptor dimerization and activation.
- To elucidate the molecular mechanisms underlying lipid-mediated regulation of EphA2 signaling.
Main Methods:
- Coarse-grain and all-atom molecular dynamics simulations were performed on a modeled EphA2 TM-full JM peptide.
- Simulations were conducted in both cholesterol-rich and cholesterol-deficient membrane environments.
Main Results:
- Cholesterol was found to stabilize specific TM dimer conformations of EphA2.
- Cholesterol enhances TM-JM interactions with the signaling lipid PIP2.
- Membrane composition significantly influences EphA2 dimerization, oligomerization, and clustering.
Conclusions:
- Cholesterol plays a critical role in stabilizing EphA2 receptor dimers and modulating its interactions with signaling lipids.
- These findings provide new insights into lipid-based regulation of EphA2, impacting receptor signaling and cancer biology.
- Understanding these lipid-receptor interactions may offer new avenues for cancer management strategies.
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