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Proteoglycan-Specific Molecular Switch for RPTPσ Clustering and Neuronal Extension

DOI: 10.1126/science.1200840 DOI Help
PMID: 21454754 PMID Help

Authors: Charlotte H. Coles (Wellcome Trust Centre for Human Genetics, University of Oxford, U.K.) , Yingjie Shen (Department of Cell Biology and Program in Neuroscience, Harvard Medical School, USA.) , Alan P Tenney (Department of Cell Biology and Program in Neuroscience, Harvard Medical School, USA.) , Christian Siebold (Wellcome Trust Centre for Human Genetics, University of Oxford, U.K.) , Geoffrey C Sutton (Wellcome Trust Centre for Human Genetics, University of Oxford, U.K.) , Weixian Lu (Wellcome Trust Centre for Human Genetics, University of Oxford, U.K) , John Gallagher (Iduron, Paterson Institute for Cancer Research, University of Manchester,) , Edith Jones (University of Oxford) , John G Flanagan (Department of Cell Biology and Program in Neuroscience, Harvard Medical School, USA.) , Alexandru Aricescu (Division of Structural Biology, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Science , VOL 332

State: Published (Approved)
Published: December 2011

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.

Journal Keywords: Animals; Axons; Binding; Cell; Cells; Cultured; Chondroitin; Chondroitin; Crystallography; X-Ray; Extracellular; Ganglia; Spinal; Glypicans; Growth; Heparan; Heparitin; Humans; Mice; Models; Biological; Models; Molecular; Neurites; Neurocan; Protein; Tertiary; Receptor-Like; Class; Sensory Receptor Cells

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: ESRF