Structural Basis for Regulation of GPR56/ADGRG1 by Its Alternatively Spliced Extracellular Domains

• Published in: Neuron (Cambridge, Mass.) Mass.), 2016-09, Vol.91 (6), p.1292-1304
• Main Authors: Salzman, Gabriel S., Ackerman, Sarah D., Ding, Chen, Koide, Akiko, Leon, Katherine, Luo, Rong, Stoveken, Hannah M., Fernandez, Celia G., Tall, Gregory G., Piao, Xianhua, Monk, Kelly R., Koide, Shohei, Araç, Demet
• Format: Article
• Language: English
• Subjects: adhesion GPCR; Alternative Splicing; Bioinformatics; Brain research; Cell Growth Processes - physiology; Crystallography; Data collection; Experiments; Fibronectin Type III Domain; Humans; Ligands; monobody; Mutation; Nervous system; oligodendrocyte development; Oligodendroglia - physiology; Packaging; protein engineering; Protein Structure, Tertiary; Proteins; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Roles; X-ray crystallography
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2016.08.022

Adhesion G protein-coupled receptors (aGPCRs) play critical roles in diverse neurobiological processes including brain development, synaptogenesis, and myelination. aGPCRs have large alternatively spliced extracellular regions (ECRs) that likely mediate intercellular signaling; however, the precise roles of ECRs remain unclear. The aGPCR GPR56/ADGRG1 regulates both oligodendrocyte and cortical development. Accordingly, human GPR56 mutations cause myelination defects and brain malformations. Here, we determined the crystal structure of the GPR56 ECR, the first structure of any complete aGPCR ECR, in complex with an inverse-agonist monobody, revealing a GPCR-Autoproteolysis-Inducing domain and a previously unidentified domain that we term Pentraxin/Laminin/neurexin/sex-hormone-binding-globulin-Like (PLL). Strikingly, PLL domain deletion caused increased signaling and characterizes a GPR56 splice variant. Finally, we show that an evolutionarily conserved residue in the PLL domain is critical for oligodendrocyte development in vivo. Thus, our results suggest that the GPR56 ECR has unique and multifaceted regulatory functions, providing novel insights into aGPCR roles in neurobiology. •Crystal structure of the entire extracellular region of GPR56, an adhesion GPCR•A unique “PLL” domain interacts extensively with a smaller-than-usual GAIN domain•PLL acts as a damper of basal activity and supports oligodendrocyte development•A monobody directed to the extracellular region allosterically inhibits signaling Salzman et al. present the first crystal structure of a complete adhesion GPCR extracellular region in complex with an allosteric inverse agonist. They reveal sites that mediate discrete receptor functions and suggest the possibility of therapeutically targeting the GPR56 extracellular region.