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Super-complexes of adhesion GPCRs and neural guidance receptors.

<div class='caption-title'>Unc5D attenuates Lphn3-FLRT2-mediated adhesion.</div>
<div class='caption-title'>FLRT2 binds cooperatively to Unc5D and Lphn3.</div>
<div class='caption-title'>Crystal structure of the tetrameric complex of FLRT2LRR and Unc5DIg and Lphn3Lec-Olf.</div>
Jackson VA, Mehmood S, Chavent M, Roversi P, Carrasquero M, Del Toro D, Seyit-Bremer G, Ranaivoson FM, Comoletti D, Sansom MS, Robinson CV, Klein R, Seiradake E
OpenAccess logo Nat Commun 7 11184 (2016)
Cited: 57 times
EuropePMC logo PMID: 27091502

Abstract

Latrophilin adhesion-GPCRs (Lphn1-3 or ADGRL1-3) and Unc5 cell guidance receptors (Unc5A-D) interact with FLRT proteins (FLRT1-3), thereby promoting cell adhesion and repulsion, respectively. How the three proteins interact and function simultaneously is poorly understood. We show that Unc5D interacts with FLRT2 in cis, controlling cell adhesion in response to externally presented Lphn3. The ectodomains of the three proteins bind cooperatively. Crystal structures of the ternary complex formed by the extracellular domains reveal that Lphn3 dimerizes when bound to FLRT2:Unc5, resulting in a stoichiometry of 1:1:2 (FLRT2:Unc5D:Lphn3). This 1:1:2 complex further dimerizes to form a larger 'super-complex' (2:2:4), using a previously undescribed binding motif in the Unc5D TSP1 domain. Molecular dynamics simulations, point-directed mutagenesis and mass spectrometry demonstrate the stability and molecular properties of these complexes. Our data exemplify how receptors increase their functional repertoire by forming different context-dependent higher-order complexes.

Reviews - 5ftt mentioned but not cited (2)

  1. Towards an Understanding of Synapse Formation. Südhof TC. Neuron 100 276-293 (2018)
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Articles - 5ftt mentioned but not cited (5)

  1. Super-complexes of adhesion GPCRs and neural guidance receptors. Jackson VA, Mehmood S, Chavent M, Roversi P, Carrasquero M, Del Toro D, Seyit-Bremer G, Ranaivoson FM, Comoletti D, Sansom MS, Robinson CV, Klein R, Seiradake E. Nat Commun 7 11184 (2016)
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Reviews citing this publication (18)

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  1. Regulation of Cerebral Cortex Folding by Controlling Neuronal Migration via FLRT Adhesion Molecules. Del Toro D, Ruff T, Cederfjäll E, Villalba A, Seyit-Bremer G, Borrell V, Klein R. Cell 169 621-635.e16 (2017)
  2. Structural Basis of Teneurin-Latrophilin Interaction in Repulsive Guidance of Migrating Neurons. Del Toro D, Carrasquero-Ordaz MA, Chu A, Ruff T, Shahin M, Jackson VA, Chavent M, Berbeira-Santana M, Seyit-Bremer G, Brignani S, Kaufmann R, Lowe E, Klein R, Seiradake E. Cell 180 323-339.e19 (2020)
  3. Transcription and Signaling Regulators in Developing Neuronal Subtypes of Mouse and Human Enteric Nervous System. Memic F, Knoflach V, Morarach K, Sadler R, Laranjeira C, Hjerling-Leffler J, Sundström E, Pachnis V, Marklund U. Gastroenterology 154 624-636 (2018)
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  6. Latrophilins: A Neuro-Centric View of an Evolutionary Conserved Adhesion G Protein-Coupled Receptor Subfamily. Moreno-Salinas AL, Avila-Zozaya M, Ugalde-Silva P, Hernández-Guzmán DA, Missirlis F, Boucard AA. Front Neurosci 13 700 (2019)
  7. Anterior Pituitary Transcriptome Suggests Differences in ACTH Release in Tame and Aggressive Foxes. Hekman JP, Johnson JL, Edwards W, Vladimirova AV, Gulevich RG, Ford AL, Kharlamova AV, Herbeck Y, Acland GM, Raetzman LT, Trut LN, Kukekova AV. G3 (Bethesda) 8 859-873 (2018)
  8. Association of Cell Adhesion Molecules Contactin-6 and Latrophilin-1 Regulates Neuronal Apoptosis. Zuko A, Oguro-Ando A, Post H, Taggenbrock RL, van Dijk RE, Altelaar AF, Heck AJ, Petrenko AG, van der Zwaag B, Shimoda Y, Pasterkamp RJ, Burbach JP. Front Mol Neurosci 9 143 (2016)
  9. Site-Specific Siderocalin Binding to Ferric and Ferric-Free Enterobactin As Revealed by Mass Spectrometry. Guo C, Steinberg LK, Cheng M, Song JH, Henderson JP, Gross ML. ACS Chem Biol 15 1154-1160 (2020)
  10. ADGRL3 rs6551665 as a Common Vulnerability Factor Underlying Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder. Kappel DB, Schuch JB, Rovaris DL, da Silva BS, Müller D, Breda V, Teche SP, S Riesgo R, Schüler-Faccini L, Rohde LA, Grevet EH, Bau CHD. Neuromolecular Med 21 60-67 (2019)
  11. LPHN2 inhibits vascular permeability by differential control of endothelial cell adhesion. Camillo C, Facchinello N, Villari G, Mana G, Gioelli N, Sandri C, Astone M, Tortarolo D, Clapero F, Gays D, Oberkersch RE, Arese M, Tamagnone L, Valdembri D, Santoro MM, Serini G. J Cell Biol 220 e202006033 (2021)
  12. A novel role for the ADHD risk gene latrophilin-3 in learning and memory in Lphn3 knockout rats. Regan SL, Pitzer EM, Hufgard JR, Sugimoto C, Williams MT, Vorhees CV. Neurobiol Dis 158 105456 (2021)
  13. GPC3-Unc5 receptor complex structure and role in cell migration. Akkermans O, Delloye-Bourgeois C, Peregrina C, Carrasquero-Ordaz M, Kokolaki M, Berbeira-Santana M, Chavent M, Reynaud F, Raj R, Agirre J, Aksu M, White ES, Lowe E, Ben Amar D, Zaballa S, Huo J, Pakos I, McCubbin PTN, Comoletti D, Owens RJ, Robinson CV, Castellani V, Del Toro D, Seiradake E. Cell 185 3931-3949.e26 (2022)
  14. Tumor-specific interendothelial adhesion mediated by FLRT2 facilitates cancer aggressiveness. Ando T, Tai-Nagara I, Sugiura Y, Kusumoto D, Okabayashi K, Kido Y, Sato K, Saya H, Navankasattusas S, Li DY, Suematsu M, Kitagawa Y, Seiradake E, Yamagishi S, Kubota Y. J Clin Invest 132 e153626 (2022)
  15. Affinity capture of polyribosomes followed by RNAseq (ACAPseq), a discovery platform for protein-protein interactions. Peng X, Emiliani F, Smallwood PM, Rattner A, Lei H, Sabbagh MF, Nathans J. Elife 7 e40982 (2018)
  16. Calcium-ligand variants of the myocilin olfactomedin propeller selected from invertebrate phyla reveal cross-talk with N-terminal blade and surface helices. Hill SE, Cho H, Raut P, Lieberman RL. Acta Crystallogr D Struct Biol 75 817-824 (2019)
  17. Native Mass Spectrometry of Iron-Sulfur Proteins. Crack JC, Le Brun NE. Methods Mol Biol 2353 231-258 (2021)
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  19. Teneurin4 dimer structures reveal a calcium-stabilized compact conformation supporting homomeric trans-interactions. Meijer DH, Frias CP, Beugelink JW, Deurloo YN, Janssen BJC. EMBO J 41 e107505 (2022)
  20. Adhesion GPCR Latrophilin 3 regulates synaptic function of cone photoreceptors in a trans-synaptic manner. Wang Y, Cao Y, Hays CL, Laboute T, Ray TA, Guerrero-Given D, Ahuja AS, Patil D, Rivero O, Kamasawa N, Kay JN, Thoreson WB, Martemyanov KA. Proc Natl Acad Sci U S A 118 e2106694118 (2021)
  21. Isoform- and ligand-specific modulation of the adhesion GPCR ADGRL3/Latrophilin3 by a synthetic binder. Kordon SP, Dutka P, Adamska JM, Bandekar SJ, Leon K, Erramilli SK, Adams B, Li J, Kossiakoff AA, Araç D. Nat Commun 14 635 (2023)
  22. Rejection of inappropriate synaptic partners in mouse retina mediated by transcellular FLRT2-UNC5 signaling. Prigge CL, Dembla M, Sharma A, El-Quessny M, Kozlowski C, Paisley CE, Miltner AM, Johnson TM, Della Santina L, Feller MB, Kay JN. Dev Cell 58 2080-2096.e7 (2023)
  23. ADGRL3 genomic variation implicated in neurogenesis and ADHD links functional effects to the incretin polypeptide GIP. Vidal OM, Vélez JI, Arcos-Burgos M. Sci Rep 12 15922 (2022)
  24. Crystal structure of LRG1 and the functional significance of LRG1 glycan for LPHN2 activation. Yang J, Yin GN, Kim DK, Han AR, Lee DS, Min KW, Fu Y, Yun J, Suh JK, Ryu JK, Kim HM. Exp Mol Med 55 1013-1022 (2023)
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  28. Design and structural characterisation of olfactomedin-1 variants as tools for functional studies. Pronker MF, van den Hoek H, Janssen BJC. BMC Mol Cell Biol 20 50 (2019)
  29. Structural insights into the formation of repulsive netrin guidance complexes. Priest JM, Nichols EL, Smock RG, Hopkins JB, Mendoza JL, Meijers R, Shen K, Özkan E. Sci Adv 10 eadj8083 (2024)
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  32. adgrl3.1-deficient zebrafish show noradrenaline-mediated externalizing behaviors, and altered expression of externalizing disorder-candidate genes, suggesting functional targets for treatment. Fontana BD, Reichmann F, Tilley CA, Lavlou P, Shkumatava A, Alnassar N, Hillman C, Karlsson KÆ, Norton WHJ, Parker MO. Transl Psychiatry 13 304 (2023)


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