biostudies-literatureJackson VANIMH NIH HHSMedical Research CouncilWellcome Trust11184https://www.ebi.ac.uk/biostudies/studies/S-EPMC4838878biostudies-literatureUnknown7Latrophilin 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 Nature communicationsSuper-complexes of adhesion GPCRs and neural guidance receptors.PMC4838878MR/L018039/1G1000819R01 MH092906WT092970MAMH092906Chavent MDel Toro DSeiradake EKlein RRanaivoson FMRobinson CVSeyit-Bremer GComoletti DSansom MSRoversi PJackson VACarrasquero MMehmood SfalseSuper-complexes of adhesion GPCRs and neural guidance receptors.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 2016-01-01T00:00:00Z2016 Apr2026-05-30T08:36:45.057Z2019-03-27T02:12:04ZS-EPMC48388782709150210.1038/ncomms11184