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Structure. 2015 Apr 7;23(4):774-81. doi: 10.1016/j.str.2015.01.013. Epub 2015 Feb 26.

Structural basis of latrophilin-FLRT interaction.

Author information

1
Department of Biochemistry, Oxford University, South Parks Road, Oxford OX1 3QU, UK.
2
Max-Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Munich-Martinsried, Germany.
3
Division of Structural Biology, Oxford University, Roosevelt Drive, Oxford OX3 7BN, UK.
4
Max-Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Munich-Martinsried, Germany; Munich Cluster for Systems Neurology (SyNergy), Feodor-Lynen-Straße 17, 81377 Munich, Germany.
5
Department of Biochemistry, Oxford University, South Parks Road, Oxford OX1 3QU, UK. Electronic address: elena.seiradake@bioch.ox.ac.uk.

Abstract

Latrophilins, receptors for spider venom α-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 β-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.

PMID:
25728924
PMCID:
PMC4396693
DOI:
10.1016/j.str.2015.01.013
[Indexed for MEDLINE]
Free PMC Article

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