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

Structure (London, England : 1993) 2015 Sep 1

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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 Ca(2+) 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. Copyright © 2015 Elsevier Ltd. All rights reserved.

Citation

Fanomezana M Ranaivoson, Qun Liu, Francesca Martini, Francesco Bergami, Sventja von Daake, Sheng Li, David Lee, Borries Demeler, Wayne A Hendrickson, Davide Comoletti. Structural and Mechanistic Insights into the Latrophilin3-FLRT3 Complex that Mediates Glutamatergic Synapse Development. Structure (London, England : 1993). 2015 Sep 1;23(9):1665-77