Proteoglycan-Specific Molecular Switch for RPTPσ Clustering and Neuronal Extension

Charlotte H Coles, Yingjie Shen, Alan P Tenney, Christian Siebold, Geoffrey C Sutton, Weixian Lu, John T Gallagher, E Yvonne Jones, John G Flanagan, Alexandru Aricescu

Research output: Contribution to journalArticlepeer-review

Abstract

Heparan and chondroitin sulfate proteoglycans (HSPGs and CSPGs, respectively) regulate numerous cell surface signaling events, with typically opposite effects on cell function. CSPGs inhibit nerve regeneration through receptor protein tyrosine phosphatase sigma (RPTPσ). Here we report that RPTPσ acts bimodally in sensory neuron extension, mediating CSPG inhibition and HSPG growth promotion. Crystallographic analyses of a shared HSPG-CSPG binding site reveal a conformational plasticity that can accommodate diverse glycosaminoglycans with comparable affinities. Heparan sulfate and analogs induced RPTPσ ectodomain oligomerization in solution, which was inhibited by chondroitin sulfate. RPTPσ and HSPGs colocalize in puncta on sensory neurons in culture, whereas CSPGs occupy the extracellular matrix. These results lead to a model where proteoglycans can exert opposing effects on neuronal extension by competing to control the oligomerization of a common receptor.
Original languageEnglish
Pages (from-to)484-488
Number of pages5
JournalScience
Volume332
Issue number6028
DOIs
Publication statusPublished - 22 Apr 2011

Keywords

  • Amino Acid Sequence
  • Animals
  • Axons
  • Binding Sites
  • Cell Membrane
  • Cells, Cultured
  • Chondroitin Sulfate Proteoglycans
  • Chondroitin Sulfates
  • Crystallography, X-Ray
  • Extracellular Matrix
  • Ganglia, Spinal
  • Glypicans
  • Growth Cones
  • Heparan Sulfate Proteoglycans
  • Heparitin Sulfate
  • Humans
  • Mice
  • Models, Biological
  • Models, Molecular
  • Molecular Sequence Data
  • Neurites
  • Neurocan
  • Protein Conformation
  • Protein Multimerization
  • Protein Structure, Tertiary
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2
  • Sensory Receptor Cells

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