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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.

Original publication

DOI

10.1038/ncomms11184

Type

Journal article

Journal

Nat Commun

Publication Date

19/04/2016

Volume

7

Keywords

Amino Acid Sequence, Animals, Cell Adhesion, Crystallography, X-Ray, HEK293 Cells, HeLa Cells, Humans, Mass Spectrometry, Membrane Glycoproteins, Mice, Knockout, Molecular Dynamics Simulation, Molecular Sequence Data, Multiprotein Complexes, Protein Binding, Protein Multimerization, Protein Structure, Secondary, Protein Structure, Tertiary, Receptors, Cell Surface, Receptors, G-Protein-Coupled, Receptors, Peptide, Sequence Homology, Amino Acid, Surface Plasmon Resonance