Journal
STRUCTURE
Volume 23, Issue 9, Pages 1665-1677Publisher
CELL PRESS
DOI: 10.1016/j.str.2015.06.022
Keywords
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Funding
- NIH [MH092906, R01AI081982, R01GM020501, R01AI101436]
- Robert Wood Johnson Foundation [67038, GM107462]
- National Science Foundation [NSF-ACI-1339649, TG-MCB070039N]
- New York Structural Biology Center at the NSLS of Brookhaven National Laboratory, a DOE facility
- NSF
- NIH/NIGMS via NSF [DMR-0936384, DMR-1332208]
- NIGMS [GM-103485]
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1450895] Funding Source: National Science Foundation
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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 beta 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.
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