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Structural Basis of Latrophilin-FLRT Interaction

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del Toro,  Daniel
Department: Molecules-Signaling-Development / Klein, MPI of Neurobiology, Max Planck Society;

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Klein,  Rüdiger
Department: Molecules-Signaling-Development / Klein, MPI of Neurobiology, Max Planck Society;

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Citation

Jackson, V. A., del Toro, D., Carrasquero, M., Roversi, P., Harlos, K., Klein, R., et al. (2015). Structural Basis of Latrophilin-FLRT Interaction. STRUCTURE, 23(4), 774-781. doi:10.1016/j.str.2015.01.013.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0026-C993-9
Abstract
Latrophilins, receptors for spider venom alpha-latrotoxin, are adhesion type G-protein-coupled receptors with emerging functions in synapse development. The N-terminal region binds the endogenous cell adhesion molecule FLRT, a major regulator of cortical and synapse development. We present crystallographic data for the mouse Latrophilin3 lectin and olfactomedin-like (Olf) domains, thereby revealing the Olf beta-propeller fold and conserved calcium-binding site. We locate the FLRT-Latrophilin binding surfaces by a combination of sequence conservation analysis, point mutagenesis, and surface plasmon resonance experiments. In stripe assays, we show that wild-type Latrophilin3 and its high-affinity interactor FLRT2, but not the binding-impaired mutants we generated, promote HeLa cell adhesion. In contrast, cortical neurons expressing endogenous FLRTs are repelled by wild-type Latrophilin3 and not by the binding-impaired mutant. Taken together, we present molecular level insights into Latrophilin structure, its FLRT-binding mechanism, and a role for Latrophilin and FLRT that goes beyond a simply adhesive interaction.