RTN4-binding proteins were widely studied as “NoGo” receptors, but their physiological interactors and roles remain elusive. Similarly, BAI adhesion-GPCRs were associated with numerous activities, but their ligands and functions remain unclear. Using unbiased approaches, we observed an unexpected convergence: RTN4 receptors are high-affinity ligands for BAI adhesion-GPCRs. A single thrombospondin type 1-repeat (TSR) domain of BAIs binds to the leucine-rich repeat domain of all three RTN4-receptor isoforms with nanomolar affinity. In the 1.65 Å crystal structure of the BAI1/RTN4-receptor complex, C-mannosylation of tryptophan and O-fucosylation of threonine in the BAI TSR-domains creates a RTN4-receptor/BAI interface shaped by unusual glycoconjugates that enables high-affinity interactions. In human neurons, RTN4 receptors regulate dendritic arborization, axonal elongation, and synapse formation by differential binding to glial versus neuronal BAIs, thereby controlling neural network activity. Thus, BAI binding to RTN4/NoGo receptors represents a receptor-ligand axis that, enabled by rare post-translational modifications, controls development of synaptic circuits.

RTN4 结合蛋白被广泛研究为“NoGo”受体，但它们的生理相互作用和作用仍然难以捉摸。同样，BAI adhesion-GPCRs 与许多活动相关，但它们的配体和功能仍不清楚。使用无偏见的方法，我们观察到一个意想不到的收敛：RTN4 受体是 BAI 粘附-GPCR 的高亲和力配体。BAI 的单个血小板反应蛋白 1 型重复 (TSR) 结构域以纳摩尔亲和力与所有三种 RTN4 受体亚型的富含亮氨酸的重复结构域结合。在 BAI1/RTN4 受体复合物的 1.65 Å 晶体结构中，BAI TSR 结构域中色氨酸的 C-甘露糖基化和苏氨酸的 O-岩藻糖基化创建了一个由不寻常的糖缀合物形成的 RTN4 受体/BAI 界面，可实现高亲和力相互作用. 在人类神经元中，RTN4 受体通过与胶质细胞和神经元 BAI 的差异结合来调节树突状树枝化、轴突伸长和突触形成，从而控制神经网络活动。因此，BAI 与 RTN4/NoGo 受体的结合代表了一个受体-配体轴，通过罕见的翻译后修饰，控制突触回路的发展。