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

Gabriel S. Salzman, Sarah D. Ackerman, Chen Ding, Akiko Koide, Katherine Leon, Rong Luo, Hannah M. Stoveken, Celia G. Fernandez, Gregory G. Tall, Xianhua Piao, Kelly R. Monk, Shohei Koide, Demet Araç

Research output: Contribution to journalArticlepeer-review

71 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1292-1304
Number of pages13
Issue number6
StatePublished - Sep 21 2016
Externally publishedYes


  • X-ray crystallography
  • adhesion GPCR
  • monobody
  • oligodendrocyte development
  • protein engineering

ASJC Scopus subject areas

  • Neuroscience(all)


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