TY - JOUR
T1 - Structural and Mechanistic Insights into the Latrophilin3-FLRT3 Complex that Mediates Glutamatergic Synapse Development
AU - Ranaivoson, Fanomezana M.
AU - Liu, Qun
AU - Martini, Francesca
AU - Bergami, Francesco
AU - Von Daake, Sventja
AU - Li, Sheng
AU - Lee, David
AU - Demeler, Borries
AU - Hendrickson, Wayne A.
AU - Comoletti, Davide
N1 - Publisher Copyright:
© 2015 Elsevier Ltd. All rightes reserved.
PY - 2015/9/1
Y1 - 2015/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84947046182&partnerID=8YFLogxK
U2 - 10.1016/j.str.2015.06.022
DO - 10.1016/j.str.2015.06.022
M3 - Article
C2 - 26235031
AN - SCOPUS:84947046182
SN - 0969-2126
VL - 23
SP - 1665
EP - 1677
JO - Structure
JF - Structure
IS - 9
ER -