Structural basis for extracellular cis and trans RPTPσ signal competition in synaptogenesis

Nat Commun. 2014 Nov 11;5:5209. doi: 10.1038/ncomms6209.

Abstract

Receptor protein tyrosine phosphatase sigma (RPTPσ) regulates neuronal extension and acts as a presynaptic nexus for multiple protein and proteoglycan interactions during synaptogenesis. Unknown mechanisms govern the shift in RPTPσ function, from outgrowth promotion to synaptic organization. Here, we report crystallographic, electron microscopic and small-angle X-ray scattering analyses, which reveal sufficient inter-domain flexibility in the RPTPσ extracellular region for interaction with both cis (same cell) and trans (opposite cell) ligands. Crystal structures of RPTPσ bound to its postsynaptic ligand TrkC detail an interaction surface partially overlapping the glycosaminoglycan-binding site. Accordingly, heparan sulphate and heparin oligomers compete with TrkC for RPTPσ binding in vitro and disrupt TrkC-dependent synaptic differentiation in neuronal co-culture assays. We propose that transient RPTPσ ectodomain emergence from the presynaptic proteoglycan layer allows capture by TrkC to form a trans-synaptic complex, the consequent reduction in RPTPσ flexibility potentiating interactions with additional ligands to orchestrate excitatory synapse formation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / physiology
  • Chick Embryo
  • Coculture Techniques
  • Crystallization
  • Extracellular Matrix Proteins / chemistry
  • Extracellular Matrix Proteins / physiology*
  • Humans
  • Ligands
  • Mice
  • Neurogenesis / physiology*
  • Neurons / cytology
  • Neurons / physiology
  • Protein Binding
  • Protein Structure, Tertiary
  • Proteoglycans / chemistry
  • Proteoglycans / physiology
  • Receptor, trkC / chemistry
  • Receptor, trkC / physiology
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / chemistry*
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / physiology*
  • Signal Transduction / physiology
  • Synapses / physiology*

Substances

  • Extracellular Matrix Proteins
  • Ligands
  • Proteoglycans
  • Receptor, trkC
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2