Sahoo Amita Rani, Bhattarai Nisha, Buck Matthias
Departments of Physiology and Biophysics, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
Departments of Physiology and Biophysics, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA; Neurosciences, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA; Pharmacology, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA; Center for Artificial Intelligence in Drug Discovery, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
Structure. 2025 Jul 3;33(7):1275-1287.e2. doi: 10.1016/j.str.2025.03.014. Epub 2025 Apr 24.
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.
EphA2跨膜受体调节细胞生长、分化和运动，其在各种癌症中的过表达使其成为临床癌症管理的潜在生物标志物。EphA2信号通过配体诱导的二聚化发生，其中跨膜（TM）和近膜（JM）结构域在稳定二聚体构象中起关键作用，从而促进信号转导。碱性JM残基与信号脂质（PIP2和PIP3）之间的静电相互作用调节磷酸化，而胆固醇在调节EphA2激活中的潜在作用仍不清楚。为了研究这一点，我们对EphA2的TM-完整JM肽进行了建模，并采用粗粒度和全原子模拟来研究其在富含胆固醇和缺乏胆固醇的膜中的二聚化。我们的研究结果表明，胆固醇稳定了特定的TM二聚体以及TM-JM与PIP2的相互作用，突出了膜组成在EphA2二聚化、寡聚化和聚集过程中的重要性。这些见解加深了我们对脂质介导的EphA2调节及其在受体信号传导和癌症进展中的意义的理解。
