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 - Funding Information:
We thank Randy Abramowitz at National Synchrotron Light Source (NSLS) beamlines X4A and X4C and the MacCHESS staff for their assistance in data collection, and the superb support provided by Virgil Schirf (CAUMA) and others of the staff at the Texas Advanced Computing Center at the University of Texas at Austin. This work was supported by NIH grants MH092906 and grant # 67038 from the Robert Wood Johnson Foundation to the Child Health Institute of New Jersey to D.C., GM107462 to W.A.H., and NIH R01AI081982 , R01GM020501 , R01AI101436 to S.L. The development of the UltraScan software is supported by National Science Foundation grant NSF-ACI-1339649 to B.D. Supercomputer time allocations were provided through National Science Foundation grant TG-MCB070039N to B.D. X4 beamlines are supported by the New York Structural Biology Center at the NSLS of Brookhaven National Laboratory , a DOE facility. CHESS is supported by the NSF and NIH/NIGMS via NSF awards DMR-0936384 and DMR-1332208 , and the MacCHESS resource is supported by NIGMS award GM-103485 . We thank other members of the Comoletti Lab, and especially Ian Hagee for his excellent technical support during protein expression and purification.
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
UR - http://www.scopus.com/inward/citedby.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
VL - 23
SP - 1665
EP - 1677
JO - Structure with Folding & design
JF - Structure with Folding & design
SN - 0969-2126
IS - 9
ER -