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Structural basis for extracellular cis and trans RPTPσ signal competition in synaptogenesis
DOI:
10.1038/ncomms6209
PMID:
25385546
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

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