title: Proteoglycan-specific molecular switch for RPTPσ clustering and neuronal extension.
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.
authors: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors: Charlotte H
authors: CH
authors: Coles
authors: Yingjie
authors: Y
authors: Shen
authors: Alan P
authors: AP
authors: Tenney
authors: Christian
authors: C
authors: Siebold
authors: Geoffrey C
authors: GC
authors: Sutton
authors: Weixian
authors: W
authors: Lu
authors: John T
authors: JT
authors: Gallagher
authors: E Yvonne
authors: EY
authors: Jones
authors: John G
authors: JG
authors: Flanagan
authors: A Radu
authors: AR
authors: Aricescu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000502:physiology*; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D011508:Chondroitin Sulfate Proteoglycans / Q000737:chemistry / Q000378:metabolism*; D002809:Chondroitin Sulfates / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D005109:Extracellular Matrix; D005727:Ganglia, Spinal; D053673:Glypicans / Q000378:metabolism; D020439:Growth Cones / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry / Q000378:metabolism*; D006497:Heparan Sulfate / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016501:Neurites / Q000502:physiology; D058580:Neurocan / Q000378:metabolism; D011487:Protein Conformation; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000737:chemistry* / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000502:physiology*
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D002809:Chondroitin Sulfates; D053673:Glypicans; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D058580:Neurocan; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2