Structural and Mechanistic Insights into the Latrophilin3-FLRT3 Complex that Mediates Glutamatergic Synapse Development

Fanomezana M. Ranaivoson, Qun Liu, Francesca Martini, Francesco Bergami, Sventja Von Daake, Sheng Li, David Lee, Borries Demeler, Wayne A. Hendrickson, Davide Comoletti

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23 Scopus citations

Abstract

Summary Latrophilins (LPHNs) are adhesion-like G-protein-coupled receptors implicated in attention-deficit/hyperactivity disorder. Recently, LPHN3 was found to regulate excitatory synapse number through trans interactions with fibronectin leucine-rich repeat transmembrane 3 (FLRT3). By isothermal titration calorimetry, we determined that only the olfactomedin (OLF) domain of LPHN3 is necessary for FLRT3 association. By multi-crystal native single-wavelength anomalous diffraction phasing, we determined the crystal structure of the OLF domain. This structure is a five-bladed β propeller with a Ca2+ ion bound in the central pore, which is capped by a mobile loop that allows the ion to exchange with the solvent. The crystal structure of the OLF/FLRT3 complex shows that LPHN3-OLF in the closed state binds with high affinity to the concave face of FLRT3-LRR with a combination of hydrophobic and charged residues. Our study provides structural and functional insights into the molecular mechanism underlying the contribution of LPHN3/FLRT3 to the development of glutamatergic synapses.

Original languageEnglish (US)
Pages (from-to)1665-1677
Number of pages13
JournalStructure
Volume23
Issue number9
DOIs
StatePublished - Sep 1 2015

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ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

Ranaivoson, F. M., Liu, Q., Martini, F., Bergami, F., Von Daake, S., Li, S., Lee, D., Demeler, B., Hendrickson, W. A., & Comoletti, D. (2015). Structural and Mechanistic Insights into the Latrophilin3-FLRT3 Complex that Mediates Glutamatergic Synapse Development. Structure, 23(9), 1665-1677. https://doi.org/10.1016/j.str.2015.06.022