RTN4/NoGo-receptor binding to BAI adhesion-GPCRs regulates neuronal development

• Published in: Cell Vol. 184; no. 24; pp. 5869 - 5885.e25
• Main Authors: Wang, Jie, Miao, Yi, Wicklein, Rebecca, Sun, Zijun, Wang, Jinzhao, Jude, Kevin M., Fernandes, Ricardo A., Merrill, Sean A., Wernig, Marius, Garcia, K. Christopher, Südhof, Thomas C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.11.2021; Elsevier
• Subjects: adhesion-GPCR; Adipokines - metabolism; Amino Acid Sequence; Angiogenesis Inhibitors - metabolism; Animals; Axons - metabolism; BAI; Brain - metabolism; C-mannosylation; Cell Adhesion; Cell Adhesion Molecules, Neuronal - metabolism; Complement C1q - metabolism; crystal structure; Dendrites - metabolism; glycoconjugates; Glycosylation; HEK293 Cells; Human Embryonic Stem Cells - metabolism; human neuron; Humans; Ligands; Mice; Mice, Inbred C57BL; morphology; Nerve Net - metabolism; Neurogenesis; neuronal network activity; neurons; Neurons - metabolism; Nogo Proteins - metabolism; NoGo receptor; Nogo Receptors - metabolism; O-fucosylation; Polysaccharides - metabolism; Protein Binding; Protein Domains; Receptors, G-Protein-Coupled - metabolism; RTN4R; Sequence Deletion; synapse; synapse formation; Synapses - metabolism; synaptic transmission; Synaptic Transmission - physiology; threonine; tryptophan; RTN4R; O-fucosylation; C-mannosylation; morphology; NoGo receptor; adhesion-GPCR; BAI; neuronal network activity; synaptic transmission; human neuron; synapse formation
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2021.10.016

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. [Display omitted] •RTN4/NoGo receptors engage in high-affinity interactions with BAI adhesion-GPCRs•RTN4/NoGo receptors bind to BAIs via a glycan-mediated interface•In neurons, interactions of RTN4Rs and BAIs control synapse and dendrite formation•Additionally, interactions of neuronal RTN4Rs with glial BAIs constrain axon growth RTN4Rs, surface proteins expressed in neurons, interact with BAI adhesion-GPCRs located in either neurons or glia via a glycan-mediated interface, and this interaction regulates the dendritic arborization, axonal elongation, and formation of synapses in cultured human neurons.