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Proteoglycan-Specific Molecular Switch for RPTPσ Clustering and Neuronal Extension

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Science  31 Mar 2011:
1200840
DOI: 10.1126/science.1200840

Abstract

Heparan and chondroitin sulfate proteoglycans (HSPGs and CSPGs) 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 analogues induced RPTPσ ectodomain oligomerization in solution, which chondroitin sulfate inhibited. 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.