2. Academic Validation
  3. Structural Basis of Latrophilin-FLRT-UNC5 Interaction in Cell Adhesion

Structural Basis of Latrophilin-FLRT-UNC5 Interaction in Cell Adhesion

  • Structure. 2015 Sep 1;23(9):1678-1691. doi: 10.1016/j.str.2015.06.024.
Yue C Lu 1,  Olha V Nazarko 1,  Richard Sando 3rd 2,  Gabriel S Salzman 1,  Nan-Sheng Li 1,  Thomas C Südhof 2,  Demet Araç 3
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, The University of Chicago, 929 East 57(th) Street, GCIS W219, Chicago, IL 60637, USA.
  • 2 Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
  • 3 Department of Biochemistry and Molecular Biology, The University of Chicago, 929 East 57(th) Street, GCIS W219, Chicago, IL 60637, USA. Electronic address: arac@uchicago.edu.
PMID: 26235030 DOI: 10.1016/j.str.2015.06.024
Abstract

Fibronectin leucine-rich repeat transmembrane proteins (FLRTs) are cell-adhesion molecules with emerging functions in cortical development and synapse formation. Their extracellular regions interact with latrophilins (LPHNs) to mediate synapse development, and with Uncoordinated-5 (UNC5)/netrin receptors to control the migration of neurons in the developing cortex. Here, we present the crystal structures of FLRT3 in isolation and in complex with LPHN3. The LPHN3/FLRT3 structure reveals that LPHN3 binds to FLRT3 at a site distinct from UNC5. Structure-based mutations specifically disrupt LPHN3/FLRT3 binding, but do not disturb their interactions with Other proteins or their cell-membrane localization. Thus, they can be used as molecular tools to dissect the functions of FLRTs and LPHNs in vivo. Our results suggest that UNC5 and LPHN3 can simultaneously bind to FLRT3, forming a trimeric complex, and that FLRT3 may form transsynaptic complexes with both LPHN3 and UNC5. These findings provide molecular insights for understanding the role of cell-adhesion proteins in synapse function.

Keywords

adhesion-type GPCR; attention deficit hyperactivity disorder; neural development; neuronal communication; synaptic junction.

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