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Nat Commun. 2014 Nov 11;5:5209. doi: 10.1038/ncomms6209.

Structural basis for extracellular cis and trans RPTPσ signal competition in synaptogenesis.

Author information

1
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
2
Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada V6T 2B5.
3
Cancer Section, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
4
Department of Molecular Physiology and Biophysics, Vanderbilt University, School of Medicine, 702 Light Hall (0615), Nashville, Tennessee 37232-0615, USA.

Abstract

Receptor protein tyrosine phosphatase sigma (RPTPσ) regulates neuronal extension and acts as a presynaptic nexus for multiple protein and proteoglycan interactions during synaptogenesis. Unknown mechanisms govern the shift in RPTPσ function, from outgrowth promotion to synaptic organization. Here, we report crystallographic, electron microscopic and small-angle X-ray scattering analyses, which reveal sufficient inter-domain flexibility in the RPTPσ extracellular region for interaction with both cis (same cell) and trans (opposite cell) ligands. Crystal structures of RPTPσ bound to its postsynaptic ligand TrkC detail an interaction surface partially overlapping the glycosaminoglycan-binding site. Accordingly, heparan sulphate and heparin oligomers compete with TrkC for RPTPσ binding in vitro and disrupt TrkC-dependent synaptic differentiation in neuronal co-culture assays. We propose that transient RPTPσ ectodomain emergence from the presynaptic proteoglycan layer allows capture by TrkC to form a trans-synaptic complex, the consequent reduction in RPTPσ flexibility potentiating interactions with additional ligands to orchestrate excitatory synapse formation.

PMID:
25385546
PMCID:
PMC4239663
DOI:
10.1038/ncomms6209
[Indexed for MEDLINE]
Free PMC Article

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