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Title: Super-complexes of adhesion GPCRs and neural guidance receptors.
Authors: Jackson, VA
Mehmood, S
Chavent, M
Roversi, P
Carrasquero, M
Del Toro, D
Seyit-Bremer, G
Ranaivoson, FM
Comoletti, D
Sansom, MSP
Robinson, CV
Klein, R
Seiradake, E
First Published: 19-Apr-2016
Publisher: Nature Research (part of Springer Nature)
Citation: Nature Communications, 2016, 7, Article number: 11184
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.
DOI Link: 10.1038/ncomms11184
eISSN: 2041-1723
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2016. This is an open-access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Description: Accession codes: The RCSB PDB accession number for the tetrameric and octameric Lphn3:FLRT2:Unc5D complexes reported in this paper are 5ftu and 5ftt, respectively. Supplementary Information accompanies this paper at
Appears in Collections:Published Articles, Dept. of Molecular and Cell Biology

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