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Proteoglycan-specific molecular switch for RPTPσ clustering and neuronal extension
DOI:
10.1126/science.1200840
PMID:
21454754
Authors:
Charlotte H.
Coles
(Wellcome Trust Centre for Human Genetics, University of Oxford)
,
Yingjie
Shen
(Harvard Medical School)
,
Alan P.
Tenney
(Harvard Medical School; Columbia University)
,
Christian
Siebold
(Wellcome Trust Centre for Human Genetics, University of Oxford)
,
Geoffrey C.
Sutton
(Wellcome Trust Centre for Human Genetics, University of Oxford)
,
Weixian
Lu
(Wellcome Trust Centre for Human Genetics, University of Oxford)
,
John T.
Gallagher
(University of Manchester)
,
E. Yvonne
Jones
(Wellcome Trust Centre for Human Genetics, University of Oxford)
,
John G.
Flanagan
(Harvard Medical School)
,
Alexandru
Aricescu
(Wellcome Trust Centre for Human Genetics, 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-Macromolecular Crystallography
Other Facilities: ESRF
Added On:
04/04/2012 12:08
Discipline Tags:
Structural biology
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)