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

Research output: Contribution to journalArticlepeer-review

38 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
Pages (from-to)1665-1677
Number of pages13
JournalStructure
Volume23
Issue number9
DOIs
StatePublished - Sep 1 2015

Fingerprint

Dive into the research topics of 'Structural and Mechanistic Insights into the Latrophilin3-FLRT3 Complex that Mediates Glutamatergic Synapse Development'. Together they form a unique fingerprint.

Cite this