The precise assembly of a functional nervous system relies on axon guidance cues. Beyond engaging their cognate receptors and initiating signaling cascades that modulate cytoskeletal dynamics, guidance cues also bind components of the extracellular matrix, notably proteoglycans, yet the role and mechanisms of these interactions remain poorly understood. We found that Drosophila secreted semaphorins bind specifically to glycosaminoglycan (GAG) chains of proteoglycans, showing a preference based on the degree of sulfation. Structural analysis of Sema2b unveiled multiple GAG-binding sites positioned outside canonical plexin-binding site, with the highest affinity binding site located at the C-terminal tail, characterized by a lysine-rich helical arrangement that appears to be conserved across secreted semaphorins. In vivo studies revealed a crucial role of the Sema2b C-terminal tail in specifying the trajectory of olfactory receptor neurons. We propose that secreted semaphorins tether to the cell surface through interactions with GAG chains of proteoglycans, facilitating their presentation to cognate receptors on passing axons.

中文翻译：

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轴突引导中蛋白聚糖介导的信号蛋白信号传导的分子机制


功能性神经系统的精确组装依赖于轴突引导线索。除了参与同源受体并启动调节细胞骨架动力学的信号级联之外，引导信号还结合细胞外基质的成分，特别是蛋白聚糖，但这些相互作用的作用和机制仍然知之甚少。我们发现果蝇分泌的信号蛋白与蛋白聚糖的糖胺聚糖 (GAG) 链特异性结合，显示出基于硫酸化程度的偏好。 Sema2b 的结构分析揭示了位于经典丛蛋白结合位点外部的多个 GAG 结合位点，其中亲和力最高的结合位点位于 C 末端尾部，其特征是富含赖氨酸的螺旋排列，似乎在分泌的信号蛋白中是保守的。体内研究揭示了 Sema2b C 末端尾部在指定嗅觉受体神经元轨迹中的关键作用。我们提出，分泌的信号蛋白通过与蛋白聚糖的 GAG 链相互作用而束缚在细胞表面，促进它们在传递轴突时呈递给同源受体。