Neuron
Volume 91, Issue 6, 21 September 2016, Pages 1292-1304
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Article
Structural Basis for Regulation of GPR56/ADGRG1 by Its Alternatively Spliced Extracellular Domains

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Highlights

  • 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

Summary

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.

Keywords

oligodendrocyte development
adhesion GPCR
monobody
X-ray crystallography
protein engineering

Cited by (0)

7

Present address: Department of Neuroscience, Yale University, New Haven, CT 06520, USA

8

Present address: Perlmutter Cancer Center and Department of Biochemistry and Molecular Pharmacology, NYU Langone Medical Center, New York, NY 10016, USA

9

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