Structural basis for LAR-RPTP/Slitrk complex-mediated synaptic adhesion

Nat Commun. 2014 Nov 14;5:5423. doi: 10.1038/ncomms6423.


Synaptic adhesion molecules orchestrate synaptogenesis. The presynaptic leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) regulate synapse development by interacting with postsynaptic Slit- and Trk-like family proteins (Slitrks), which harbour two extracellular leucine-rich repeats (LRR1 and LRR2). Here we identify the minimal regions of the LAR-RPTPs and Slitrks, LAR-RPTPs Ig1-3 and Slitrks LRR1, for their interaction and synaptogenic function. Subsequent crystallographic and structure-guided functional analyses reveal that the splicing inserts in LAR-RPTPs are key molecular determinants for Slitrk binding and synapse formation. Moreover, structural comparison of the two Slitrk1 LRRs reveal that unique properties on the concave surface of Slitrk1 LRR1 render its specific binding to LAR-RPTPs. Finally, we demonstrate that lateral interactions between adjacent trans-synaptic LAR-RPTPs/Slitrks complexes observed in crystal lattices are critical for Slitrk1-induced lateral assembly and synaptogenic activity. Thus, we propose a model in which Slitrks mediate synaptogenic functions through direct binding to LAR-RPTPs and the subsequent lateral assembly of LAR-RPTPs/Slitrks complexes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cell Adhesion / physiology
  • HEK293 Cells
  • Hippocampus / cytology
  • Humans
  • Membrane Proteins / metabolism
  • Membrane Proteins / physiology*
  • Nerve Tissue Proteins / metabolism
  • Nerve Tissue Proteins / physiology*
  • Protein Structure, Tertiary
  • Protein Tyrosine Phosphatases / metabolism
  • Protein Tyrosine Phosphatases / physiology*
  • Rats
  • Real-Time Polymerase Chain Reaction
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / metabolism
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / physiology*
  • Repressor Proteins / metabolism
  • Repressor Proteins / physiology
  • Synapses / metabolism*
  • Synapses / physiology


  • LRR1 protein, human
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Repressor Proteins
  • SLITRK1 protein, human
  • Protein Tyrosine Phosphatases
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2

Associated data

  • PDB/4RCA
  • PDB/4RCW