title: Structural and Mechanistic Insights into the Latrophilin3-FLRT3 Complex that Mediates Glutamatergic Synapse Development.
abstract: 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.
authors.affiliation: Child Health Institute of New Jersey and Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, 89 French Street, New Brunswick, NJ 08901, USA.
authors.forename: Fanomezana M
authors.initials: FM
authors.lastname: Ranaivoson
authors.affiliation: New York Structural Biology Center, NSLSII, Brookhaven National Laboratory, Upton, NY 11973, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Child Health Institute of New Jersey and Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, 89 French Street, New Brunswick, NJ 08901, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Martini
authors.affiliation: Child Health Institute of New Jersey and Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, 89 French Street, New Brunswick, NJ 08901, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bergami
authors.affiliation: Child Health Institute of New Jersey and Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, 89 French Street, New Brunswick, NJ 08901, USA.
authors.forename: Sventja
authors.initials: S
authors.lastname: von Daake
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lee
authors.affiliation: The University of Texas Health Science Center at San Antonio, Department of Biochemistry, San Antonio, TX 78229, USA.
authors.forename: Borries
authors.initials: B
authors.lastname: Demeler
authors.affiliation: New York Structural Biology Center, NSLSII, Brookhaven National Laboratory, Upton, NY 11973, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Hendrickson
authors.affiliation: Child Health Institute of New Jersey and Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, 89 French Street, New Brunswick, NJ 08901, USA; Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901, USA. Electronic address: comoleda@rwjms.rutgers.edu.
authors.forename: Davide
authors.initials: D
authors.lastname: Comoletti
mesh_terms: D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D018360:Crystallography, X-Ray; D018698:Glutamic Acid / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000378:metabolism*; D018000:Receptors, Peptide / Q000737:chemistry* / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
chemical_list: D002118:Calcium; D018698:Glutamic Acid; D008562:Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; C514260:FLRT3 protein, mouse; C000592543:Adgrl3 protein, mouse