Super-complexes of adhesion GPCRs and neural guidance receptors

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, Carol V. Robinson, Rüdiger Klein and Elena Seiradake ()
Additional contact information
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
Davide Comoletti: Child Health Institute of New Jersey, 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
Elena Seiradake: Oxford University

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11184

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