Proteoglycan-Specific Molecular Switch for RPTP[sigma] Clustering and Neuronal Extension

• Published in: Science (American Association for the Advancement of Science) Vol. 332; no. 6028; p. 484
• Main Authors: Coles, Charlotte H, Shen, Yingjie, Tenney, Alan P, Siebold, Christian, Sutton, Geoffrey C, Lu, Weixian, Gallagher, John T, Jones, E Yvonne, Flanagan, John G, A. Radu Aricescu
• Format: Journal Article
• Language: English
• Published: Washington The American Association for the Advancement of Science 22.04.2011
• Subjects: Cells; Cluster analysis; Molecular chemistry; Neurons
• DOI: 10.1126/science.1200840
• ISSN: 0036-8075

As axons extend outward, whether in the course of normal development or in regenerating after damage, they encounter an environment that includes proteoglycans. The chondroitin sulfate proteoglycans tend to inhibit axon growth, and the heparan sulfate proteoglycans tend to have the opposite effect. Both proteoglycans can signal through the same receptor, RPTP-σ. Studying neurons from the mouse dorsal root ganglion, Coles et al. (p. 484, published online 31 March) found that both types of proteoglycan used the same binding site on the receptor. However, heparan sulfate binding leads to receptor oligomerization, unlike chondroitin sulfate. Clustering of the receptors thus appears to generate an environment that encourages axonal growth. 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. [PUBLICATION ABSTRACT]