Understanding the Structural Basis of Adhesion GPCR Functions

  • Demet Araç
  • Norbert Sträter
  • Elena Seiradake
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 234)

Graphical Abstract


Unlike conventional G-protein-coupled receptors (GPCRs), adhesion GPCRs (aGPCRs) have large extracellular regions that are autoproteolytically cleaved from their membrane-embedded seven-pass transmembrane helices. Autoproteolysis occurs within the conserved GPCR-Autoproteolysis INducing (GAIN) domain that is juxtaposed to the transmembrane domain and cleaves the last beta strand of the GAIN domain. The other domains of the extracellular region are variable and specific to each aGPCR and are likely involved in adhering to various ligands. Emerging evidence suggest that extracellular regions may modulate receptor function and that ligand binding to the extracellular regions may induce receptor activation via multiple mechanisms. Here, we summarize current knowledge about the structural understanding for the extracellular regions of aGPCRs and discuss their possible functional roles that emerge from the available structural information.


GAIN Horm Olfactomedin Lectin Stachel Tethered agonist Unc5 FLRT Super-complex Latrophilin 



We would like to thank Gabriel Salzman (University of Chicago) for his help with some of the figures and critical reading of the manuscript. Supported by grants from the Brain Research Foundation (to D.A.) and Big Ideas Generator (to D.A.). N.S. thanks the Deutsche Forschungsgemeinschaft for support in the Research Unit 2149 (Project 5, STR 477/15-1). E.S. was supported by the UK Medical Research Council (MR/L018039/1).


  1. 1.
    Araç D, Boucard AA, Bolliger MF, Nguyen J, Soltis SM, Südhof TC et al (2012) A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis. EMBO J 31:1364–1378. doi: 10.1038/emboj.2012.26 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Liebscher I, Schön J, Petersen SC, Fischer L, Auerbach N, Demberg LM et al (2014) A tethered agonist within the ectodomain activates the adhesion G protein-coupled receptors GPR126 and GPR133. Cell Rep 9:2018–2026. doi: 10.1016/j.celrep.2014.11.036 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Stoveken HM, Hajduczok AG, Xu L, Tall GG (2015) Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist. Proc Natl Acad Sci U S A 112:6194–6199. doi: 10.1073/pnas.1421785112 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Demberg LM, Rothemund S, Schöneberg T, Liebscher I (2015) Identification of the tethered peptide agonist of the adhesion G protein-coupled receptor GPR64/ADGRG2. Biochem Biophys Res Commun 464:743–747. doi: 10.1016/j.bbrc.2015.07.020 CrossRefPubMedGoogle Scholar
  5. 5.
    Wilde C, Fischer L, Lede V, Kirchberger J, Rothemund S, Schöneberg T et al (2016) The constitutive activity of the adhesion GPCR GPR114/ADGRG5 is mediated by its tethered agonist. FASEB J 30:666–673. doi: 10.1096/fj.15-276220 CrossRefPubMedGoogle Scholar
  6. 6.
    Vakonakis I, Langenhan T, Prömel S, Russ A, Campbell ID (2008) Solution structure and sugar-binding mechanism of mouse latrophilin-1 RBL: a 7TM receptor-attached lectin-like domain. Structure 16:944–953. doi: 10.1016/j.str.2008.02.020 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Jackson VA, del Toro D, Carrasquero M, Roversi P, Harlos K, Klein R et al (2015) Structural basis of latrophilin-FLRT interaction. Structure 23:774–781. doi: 10.1016/j.str.2015.01.013 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ranaivoson FM, Liu Q, Martini F, Bergami F, von Daake S, Li S et al (2015) Structural and mechanistic insights into the latrophilin3-FLRT3 complex that mediates glutamatergic synapse development. Structure 23:1665–1677. doi: 10.1016/j.str.2015.06.022 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Lu YC, Nazarko OV, Sando R, Salzman GS, Südhof TC, Araç D (2015) Structural basis of latrophilin-FLRT-UNC5 interaction in cell adhesion. Structure 23:1678–1691. doi: 10.1016/j.str.2015.06.024 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Jackson VA, Mehmood S, Chavent M, Roversi P, Carrasquero M, del Toro D et al (2016) Super-complexes of adhesion GPCRs and neural guidance receptors. Nat Commun 7:11184CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Krasnoperov VG, Bittner MA, Beavis R, Kuang Y, Salnikow KV, Chepurny OG et al (1997) alpha-Latrotoxin stimulates exocytosis by the interaction with a neuronal G-protein-coupled receptor. Neuron 18:925–937CrossRefPubMedGoogle Scholar
  12. 12.
    Lin H-H, Chang G-W, Davies JQ, Stacey M, Harris J, Gordon S (2004) Autocatalytic cleavage of the EMR2 receptor occurs at a conserved G protein-coupled receptor proteolytic site motif. J Biol Chem 279:31823–31832. doi: 10.1074/jbc.M402974200 CrossRefPubMedGoogle Scholar
  13. 13.
    Krishnan A, Nijmeijer S, de Graaf C, Schiöth HB (2016) Classification, nomenclature and structural aspects of adhesion GPCRs. In: Langenhan T, Schöneberg T (eds) Adhesion G protein-coupled receptors: molecular, physiological and pharmacological principles in health and disease. Springer, HeidelbergGoogle Scholar
  14. 14.
    Gray JX, Haino M, Roth MJ, Maguire JE, Jensen PN, Yarme A et al (1996) CD97 is a processed, seven-transmembrane, heterodimeric receptor associated with inflammation. J Immunol 157:5438–5447PubMedGoogle Scholar
  15. 15.
    Shashidhar S, Lorente G, Nagavarapu U, Nelson A, Kuo J, Cummins J et al (2005) GPR56 is a GPCR that is overexpressed in gliomas and functions in tumor cell adhesion. Oncogene 24:1673–1682. doi: 10.1038/sj.onc.1208395 CrossRefPubMedGoogle Scholar
  16. 16.
    Stacey M, Chang G-W, Sanos SL, Chittenden LR, Stubbs L, Gordon S et al (2002) EMR4, a novel epidermal growth factor (EGF)-TM7 molecule up-regulated in activated mouse macrophages, binds to a putative cellular ligand on B lymphoma cell line A20. J Biol Chem 277:29283–29293. doi: 10.1074/jbc.M204306200 CrossRefPubMedGoogle Scholar
  17. 17.
    Liebscher I, Schöneberg T (2016) Tethered agonism: a common activation mechanism of adhesion GPCRs. In: Langenhan T, Schöneberg T (eds) Adhesion G protein-coupled receptors: molecular, physiological and pharmacological principles in health and disease. Springer, HeidelbergGoogle Scholar
  18. 18.
    Kishore A, Hall RA (2016) Versatile signaling activity of adhesion GPCRs. In: Langenhan T, Schöneberg T (eds) Adhesion G protein-coupled receptors: molecular, physiological and pharmacological principles in health and disease. Springer, HeidelbergGoogle Scholar
  19. 19.
    Nieberler M, Kittel RJ, Petrenko AG, Lin H-H, Langenhan T (2016) Control of adhesion GPCR function through proteolytic processing. In: Langenhan T, Schöneberg T (eds) Adhesion G protein-coupled receptors: molecular, physiological and pharmacological principles in health and disease. Springer, HeidelbergGoogle Scholar
  20. 20.
    Sigoillot SM, Monk KR, Piao X, Selimi F, Harty BL (2016) Adhesion G protein-coupled receptors in the nervous system: from synapse and dendrite morphogenesis to myelination. In: Langenhan T, Schöneberg T (eds) Adhesion G protein-coupled receptors: molecular, physiological and pharmacological principles in health and disease. Springer, HeidelbergGoogle Scholar
  21. 21.
    Kan Z, Jaiswal BS, Stinson J, Janakiraman V, Bhatt D, Stern HM et al (2010) Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 466:869–873. doi: 10.1038/nature09208 CrossRefPubMedGoogle Scholar
  22. 22.
    Arcos-Burgos M, Jain M, Acosta MT, Shively S, Stanescu H, Wallis D et al (2010) A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication. Mol Psychiatry 15:1053–1066. doi: 10.1038/mp.2010.6 CrossRefPubMedGoogle Scholar
  23. 23.
    Paavola KJ, Stephenson JR, Ritter SL, Alter SP, Hall RA (2011) The N terminus of the adhesion G protein-coupled receptor GPR56 controls receptor signaling activity. J Biol Chem 286:28914–28921. doi: 10.1074/jbc.M111.247973 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Yang L, Chen G, Mohanty S, Scott G, Fazal F, Rahman A et al (2011) GPR56 regulates VEGF production and angiogenesis during melanoma progression. Cancer Res 71:5558–5568. doi: 10.1158/0008-5472.CAN-10-4543 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Grace CRR, Perrin MH, Gulyas J, Digruccio MR, Cantle JP, Rivier JE et al (2007) Structure of the N-terminal domain of a type B1 G protein-coupled receptor in complex with a peptide ligand. Proc Natl Acad Sci U S A 104:4858–4863. doi: 10.1073/pnas.0700682104 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Hoare SRJ (2005) Mechanisms of peptide and nonpeptide ligand binding to Class B G-protein-coupled receptors. Drug Discov Today 10:417–427. doi: 10.1016/S1359-6446(05)03370-2 CrossRefPubMedGoogle Scholar
  27. 27.
    Bjarnadóttir TK, Fredriksson R, Höglund PJ, Gloriam DE, Lagerström MC, Schiöth HB (2004) The human and mouse repertoire of the adhesion family of G-protein-coupled receptors. Genomics 84:23–33. doi: 10.1016/j.ygeno.2003.12.004 CrossRefPubMedGoogle Scholar
  28. 28.
    Davletov BA, Shamotienko OG, Lelianova VG, Grishin EV, Ushkaryov YA (1996) Isolation and biochemical characterization of a Ca2+-independent alpha-latrotoxin-binding protein. J Biol Chem 271:23239–23245CrossRefPubMedGoogle Scholar
  29. 29.
    Silva J-P, Lelianova VG, Ermolyuk YS, Vysokov N, Hitchen PG, Berninghausen O et al (2011) Latrophilin 1 and its endogenous ligand Lasso/teneurin-2 form a high-affinity transsynaptic receptor pair with signaling capabilities. Proc Natl Acad Sci U S A 108:12113–12118. doi: 10.1073/pnas.1019434108 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Boucard AA, Ko J, Südhof TC (2012) High affinity neurexin binding to cell adhesion G-protein-coupled receptor CIRL1/latrophilin-1 produces an intercellular adhesion complex. J Biol Chem 287:9399–9413. doi: 10.1074/jbc.M111.318659 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    O’Sullivan ML, de Wit J, Savas JN, Comoletti D, Otto-Hitt S, Yates JR et al (2012) FLRT proteins are endogenous latrophilin ligands and regulate excitatory synapse development. Neuron 73:903–910. doi: 10.1016/j.neuron.2012.01.018 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Seiradake E, del Toro D, Nagel D, Cop F, Härtl R, Ruff T et al (2014) FLRT structure: balancing repulsion and cell adhesion in cortical and vascular development. Neuron 84:370–385. doi: 10.1016/j.neuron.2014.10.008 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Yamagishi S, Hampel F, Hata K, Del Toro D, Schwark M, Kvachnina E et al (2011) FLRT2 and FLRT3 act as repulsive guidance cues for Unc5-positive neurons. EMBO J 30:2920–2933. doi: 10.1038/emboj.2011.189 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJE (2015) The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc 10:845–858. doi: 10.1038/nprot.2015.053 CrossRefPubMedGoogle Scholar
  35. 35.
    Wouters MA, Rigoutsos I, Chu CK, Feng LL, Sparrow DB, Dunwoodie SL (2005) Evolution of distinct EGF domains with specific functions. Protein Sci 14:1091–1103. doi: 10.1110/ps.041207005 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Handford P, Downing AK, Rao Z, Hewett DR, Sykes BC, Kielty CM (1995) The calcium binding properties and molecular organization of epidermal growth factor-like domains in human fibrillin-1. J Biol Chem 270:6751–6756CrossRefPubMedGoogle Scholar
  37. 37.
    Scholz N, Gehring J, Guan C, Ljaschenko D, Fischer R, Lakshmanan V et al (2015) The adhesion GPCR latrophilin/CIRL shapes mechanosensation. Cell Rep 11:866–874. doi: 10.1016/j.celrep.2015.04.008 CrossRefPubMedGoogle Scholar
  38. 38.
    Hamann J, Aust G, Araç D, Engel FB, Formstone C, Fredriksson R et al (2015) International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors. Pharmacol Rev 67:338–367. doi: 10.1124/pr.114.009647 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Zhang D, Zhao Q, Wu B (2015) Structural studies of G protein-coupled receptors. Mol Cells 38:836–842, doi:10.14348/molcells.2015.0263CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2016

Authors and Affiliations

  • Demet Araç
    • 1
  • Norbert Sträter
    • 2
  • Elena Seiradake
    • 3
  1. 1.Department of Biochemistry and Molecular BiologyUniversity of ChicagoChicagoUSA
  2. 2.Institute for Bioanalytical Chemistry, Leipzig UniversityLeipzigGermany
  3. 3.Department of BiochemistryUniversity of OxfordOxfordUK

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