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Super-complexes of adhesion GPCRs and neural guidance receptors

Author

Listed:
  • Verity A. Jackson

    (Oxford University)

  • Shahid Mehmood

    (University of Oxford)

  • Matthieu Chavent

    (Oxford University)

  • Pietro Roversi

    (Oxford University)

  • Maria Carrasquero

    (Oxford University)

  • Daniel del Toro

    (Max-Planck Institute of Neurobiology)

  • Goenuel Seyit-Bremer

    (Max-Planck Institute of Neurobiology)

  • Fanomezana M. Ranaivoson

    (Child Health Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University
    Rutgers University
    Robert Wood Johnson Medical School, Rutgers University)

  • Davide Comoletti

    (Child Health Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University
    Rutgers University
    Robert Wood Johnson Medical School, Rutgers University)

  • Mark S. P. Sansom

    (Oxford University)

  • Carol V. Robinson

    (University of Oxford)

  • Rüdiger Klein

    (Max-Planck Institute of Neurobiology
    Munich Cluster for Systems Neurology (SyNergy))

  • Elena Seiradake

    (Oxford University)

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.

Suggested Citation

  • Verity A. Jackson & Shahid Mehmood & Matthieu Chavent & Pietro Roversi & Maria Carrasquero & Daniel del Toro & Goenuel Seyit-Bremer & Fanomezana M. Ranaivoson & Davide Comoletti & Mark S. P. Sansom & , 2016. "Super-complexes of adhesion GPCRs and neural guidance receptors," Nature Communications, Nature, vol. 7(1), pages 1-13, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11184
    DOI: 10.1038/ncomms11184
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    Cited by:

    1. Szymon P. Kordon & Przemysław Dutka & Justyna M. Adamska & Sumit J. Bandekar & Katherine Leon & Satchal K. Erramilli & Brock Adams & Jingxian Li & Anthony A. Kossiakoff & Demet Araç, 2023. "Isoform- and ligand-specific modulation of the adhesion GPCR ADGRL3/Latrophilin3 by a synthetic binder," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Christos Gogou & J. Wouter Beugelink & Cátia P. Frias & Leanid Kresik & Natalia Jaroszynska & Uwe Drescher & Bert J. C. Janssen & Robert Hindges & Dimphna H. Meijer, 2024. "Alternative splicing controls teneurin-3 compact dimer formation for neuronal recognition," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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