TAM受体-配体界面的进化调优凸显与再生吞噬信号相关的静电特征
Evolutionary tuning of TAM receptor-ligand interfaces highlights electrostatic features associated with regenerative phagocytic signaling
AI总结：
通过进化调优揭示TAM受体-配体界面的静电特征，为再生吞噬信号的物种特异性调节提供保守框架。
摘要：
高效解决神经炎症和碎片清除是中枢神经系统再生成功的关键决定因素。再生脊椎动物如斑马鱼往往比哺乳动物表现出更快的免疫消退和碎片清除，但这些差异的分子决定因素仍不完全清楚。TAM受体酪氨酸激酶（Tyro3、Axl和Mertk）及其配体Gas6和蛋白质S是神经系统吞噬和免疫消退的核心调节因子，但这些受体-配体复合物的内在结构特性是否有助于再生效率尚未系统性探索。在这里，我们对斑马鱼、人类和小鼠的TAM受体和配体进行了比较的计算机分析，整合了序列进化、高置信度结构建模、界面表征和静电分析。尽管序列差异显著，配体结合域显示出强结构保守性，支持TAM-配体相互作用的保守全球模式。在界面层面，斑马鱼复合物表现出增强的静电贡献和增加的盐桥密度，特别是在Tyro3-蛋白质S相互作用中。残基层面的静电分析揭示了在物种间空间保守的界面热点区域，尽管个体接触的进化重新排列。这些结果表明，TAM受体-配体界面通过细微的静电和几何优化而非大规模结构变化进行进化调优，提供了一个保守且可适应的框架，用于物种特异性调节吞噬信号。
英文摘要：
Efficient resolution of neuroinflammation and debris clearance is a key determinant of successful central nervous system regeneration. Regenerative vertebrates such as Danio rerio often exhibit faster immune resolution and debris clearance than mammals, yet the molecular determinants underlying these differences remain incompletely understood. TAM receptor tyrosine kinases (Tyro3, Axl, and Mertk) and their ligands Gas6 and Protein S are central regulators of phagocytosis and immune resolution in the nervous system, but whether intrinsic structural properties of these receptor-ligand complexes contribute to regenerative efficiency has not been systematically explored. Here, we present a comparative in silico analysis of TAM receptors and ligands from zebrafish, human, and mouse, integrating sequence evolution, high-confidence structural modeling, interface characterization, and electrostatic analysis. Despite substantial sequence divergence, ligand-binding domains display strong structural conservation, supporting a conserved global mode of TAM-ligand engagement. At the interface level, zebrafish complexes show enhanced electrostatic contributions and increased salt-bridge density, particularly in the Tyro3-Protein S interaction. Residue-level electrostatic analysis reveals clustered interface hotspots that are spatially conserved across species despite evolutionary rewiring of individual contacts. Together, these results suggest that TAM receptor-ligand interfaces are evolutionarily tuned through subtle electrostatic and geometric optimization rather than large-scale structural changes, providing a conserved yet adaptable framework for species-specific modulation of phagocytic signaling.
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