5kvm
Extracellular region of mouse GPR56/ADGRG1 in complex with FN3 monobody
Structural highlights
FunctionAGRG1_MOUSE Receptor involved in cell adhesion and probably in cell-cell interactions. Mediates cell matrix adhesion in developing neurons and hematopoietic stem cells. Receptor for collagen III/COL3A1 in the developing brain and involved in regulation of cortical development, specifically in maintenance of the pial basement membrane integrity and in cortical lamination (PubMed:21768377). Binding to the COL3A1 ligand inhibits neuronal migration and activates the RhoA pathway by coupling to GNA13 and possibly GNA12 (By similarity). Plays a role in the maintenance of hematopoietic stem cells and/or leukemia stem cells in bone marrow niche (PubMed:23478665). Plays a critical role in tumourigenesis (By similarity). Plays essential role in testis development (PubMed:20981830).[UniProtKB:Q9Y653][1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedAdhesion 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. Structural Basis for Regulation of GPR56/ADGRG1 by Its Alternatively Spliced Extracellular Domains.,Salzman GS, Ackerman SD, Ding C, Koide A, Leon K, Luo R, Stoveken HM, Fernandez CG, Tall GG, Piao X, Monk KR, Koide S, Arac D Neuron. 2016 Sep 21;91(6):1292-1304. doi: 10.1016/j.neuron.2016.08.022. PMID:27657451[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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