Structural Basis of Teneurin-Latrophilin Interaction in Repulsive Guidance of Migrating Neurons
Structural Basis of Teneurin-Latrophilin Interaction in Repulsive Guidance of Migrating Neurons
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DOI：
10.1016/j.cell.2019.12.014
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发表时间：
2020-01-23
期刊：
影响因子：
64.5
通讯作者：
Seiradake, Elena
中科院分区：
文献类型：
--
作者：
del Toro, Daniel;Carrasquero-Ordaz, Maria A.;Seiradake, Elena
腱鞘蛋白是古老的后生动物细胞粘附受体，在高等动物中控制大脑发育和神经元连接。细胞外C端结合粘附GPCR亲Latrophilin，形成具有突触形成功能的跨细胞复合体。然而，teneurin、Latrophilins和FLRT蛋白也在小鼠早期发育阶段的皮质细胞迁移过程中表达。在这里，我们展示了Teneurin-Latrophilin复合物的晶体结构，揭示了亲Latrophilin的凝集素和嗅素结构域是如何通过Teneurin的螺旋β -桶结构域（YD外壳）结合的。我们将基于结构的蛋白质工程与生物物理分析、细胞迁移分析和子宫内电穿孔实验相结合，以探讨相互作用在皮层神经元迁移中的重要性。研究表明，嗜碱蛋白与teneurin和flrt的结合通过接触排斥依赖机制指导神经元的迁移。这种作用是在细胞体和小神经突而不是它们的突上观察到的。结果举例说明了结构编码的突触原蛋白复合体如何也用于排斥性细胞引导。
Teneurins are ancient metazoan cell adhesion receptors that control brain development and neuronal wiring in higher animals. The extracellular C terminus binds the adhesion GPCR Latrophilin, forming a trans-cellular complex with synaptogenic functions. However, Teneurins, Latrophilins, and FLRT proteins are also expressed during murine cortical cell migration at earlier developmental stages. Here, we present crystal structures of Teneurin-Latrophilin complexes that reveal how the lectin and olfactomedin domains of Latrophilin bind across a spiraling beta-barrel domain of Teneurin, the YD shell. We couple structure-based protein engineering to biophysical analysis, cell migration assays, and in utero electroporation experiments to probe the importance of the interaction in cortical neuron migration. We show that binding of Latrophilins to Teneurins and FLRTs directs the migration of neurons using a contact repulsion-dependent mechanism. The effect is observed with cell bodies and small neurites rather than their processes. The results exemplify how a structure-encoded synaptogenic protein complex is also used for repulsive cell guidance.