Cholesterol-dependent dimerization and conformational dynamics of EphA2 receptors from coarse-grained and all-atom simulations

IF 4.4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Structure Pub Date : 2025-04-24 DOI:10.1016/j.str.2025.03.014

Amita Rani Sahoo, Nisha Bhattarai, Matthias Buck

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引用次数: 0

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.

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来自粗粒度和全原子模拟的EphA2受体的胆固醇依赖性二聚化和构象动力学

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体发生，其中跨膜结构域（TM）和近膜结构域（JM）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残基和信号脂质（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激活中的潜在作用尚不清楚。为了研究这一点，我们模拟了EphA2的TM-full JM肽，并采用粗粒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，胆固醇稳定了特异性TM二聚体和TM- jm与PIP2的相互作用，强调了膜组成在EphA2二聚、寡聚和聚类中的重要性。这些见解增强了我们对脂质介导的EphA2调控及其在受体信号传导和癌症进展中的意义的理解。

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来源期刊

Structure 生物-生化与分子生物学

CiteScore

8.90

自引率

1.80%

发文量

155

审稿时长

3-8 weeks

期刊介绍： Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.