title: Structural Basis for Regulation of GPR56/ADGRG1 by Its Alternatively Spliced Extracellular Domains.
abstract: 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.
authors.affiliation: Biophysical Sciences Program, The University of Chicago, Chicago, IL 60637, USA; Medical Scientist Training Program, The University of Chicago, Chicago, IL 60637, USA; Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Gabriel S
authors.initials: GS
authors.lastname: Salzman
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Sarah D
authors.initials: SD
authors.lastname: Ackerman
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Ding
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Koide
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Leon
authors.affiliation: Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Luo
authors.affiliation: Departments of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Stoveken
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Celia G
authors.initials: CG
authors.lastname: Fernandez
authors.affiliation: Departments of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Tall
authors.affiliation: Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Xianhua
authors.initials: X
authors.lastname: Piao
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Monk
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA. Electronic address: shohei.koide@nyumc.org.
authors.forename: Shohei
authors.initials: S
authors.lastname: Koide
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA. Electronic address: arac@uchicago.edu.
authors.forename: Demet
authors.initials: D
authors.lastname: Araç
mesh_terms: D017398:Alternative Splicing; D048708:Cell Growth Processes / Q000502:physiology; D000071238:Fibronectin Type III Domain; D006801:Humans; D009836:Oligodendroglia / Q000502:physiology*; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D043562:Receptors, G-Protein-Coupled; C524781:Adgrg1 protein, mouse
keywords: X-ray crystallography; adhesion GPCR; monobody; oligodendrocyte development; protein engineering