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

doi:10.1016/j.str.2015.06.022

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

Chemistry and Biochemistry

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	1665-1677
Number of pages	13
Journal	Structure
Volume	23
Issue number	9
DOIs	https://doi.org/10.1016/j.str.2015.06.022
State	Published - Sep 1 2015

Funding

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.

Funders	Funder number
R01AI081982, R01AI101436
DMR-1332208, DMR-0936384
New York Structural Biology Center
NSF-ACI-1339649, TG-MCB070039N
67038, MH092906
GM-103485, R01GM020501, R01GM107462
Robert Wood Johnson Foundation

Access to Document

10.1016/j.str.2015.06.022

Cite this

@article{88e4b928536f415d81fb81e36342f741,

title = "Structural and Mechanistic Insights into the Latrophilin3-FLRT3 Complex that Mediates Glutamatergic Synapse Development",

abstract = "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.",

author = "Ranaivoson, \{Fanomezana M.\} and Qun Liu and Francesca Martini and Francesco Bergami and \{Von Daake\}, Sventja and Sheng Li and David Lee and Borries Demeler and Hendrickson, \{Wayne A.\} and Davide Comoletti",

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Ltd. All rightes reserved.",

year = "2015",

month = sep,

day = "1",

doi = "10.1016/j.str.2015.06.022",

language = "English",

volume = "23",

pages = "1665--1677",

journal = "Structure",

issn = "0969-2126",

publisher = "Cell Press",

number = "9",

}

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

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 - https://www.scopus.com/pages/publications/84947046182

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 -

Structural and Mechanistic Insights into the Latrophilin3-FLRT3 Complex that Mediates Glutamatergic Synapse Development

Abstract

Funding

Access to Document

Other files and links

Fingerprint

Cite this