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

DOI: 10.1038/ncomms6209 DOI Help
PMID: 25385546 PMID Help

Authors: Charlotte H Coles (Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford) , Nikolaos Mitakidis (Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford) , Peng Zhang (Brain Research Centre and Department of Psychiatry, University of British Columbia) , Jonathan Elegheert (Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford) , Weixian Lu (Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford) , Andrew W. Stoker (Cancer Section, Institute of Child Health, University College London) , Terunaga Nakagawa (Department of Molecular Physiology and Biophysics, Vanderbilt University, School of Medicine) , Ann Marie Craig (Brain Research Centre and Department of Psychiatry, University of British Columbia) , E. Yvonne Jones (University of Oxford) , A. Radu Aricescu (Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 5

State: Published (Approved)
Published: November 2014
Diamond Proposal Number(s): 8423

Open Access Open Access

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.

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Other Facilities: ESRF (beamlines ID29 and BM29)

Documents:
ncomms6209.pdf