期刊
STRUCTURE
卷 23, 期 4, 页码 774-781出版社
CELL PRESS
DOI: 10.1016/j.str.2015.01.013
关键词
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资金
- UK Medical Research Council [MR/L018039/1, G0900084, G1000099]
- Max-Planck Society
- Deutsche Forschungsgemeinschaft [SFB 834, EXC 115]
- Marie Curie IEF fellowship [ID 274541]
- Wellcome Trust DPhil studentship
- Medical Research Council [G1100525, G1000099, MR/M000141/1, MR/L018039/1, MR/N00065X/1, G0900084] Funding Source: researchfish
- MRC [MR/M000141/1, G0900084, MR/L018039/1, MR/N00065X/1, G1000099] Funding Source: UKRI
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.
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