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

Charlotte H. Coles, Nikolaos Mitakidis, Peng Zhang, Jonathan Elegheert, Weixian Lu, Andrew W. Stoker, Terunaga Nakagawa, Ann Marie Craig, E. Yvonne Jones, A. Radu Aricescu
Nat Commun. 2014-11-11; 5(1):
DOI: 10.1038/ncomms6209

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

Structural basis for extracellular cis and trans RPTPσ signal competition in

Coles CH(1), Mitakidis N(1), Zhang P(2), Elegheert J(1), Lu W(1), Stoker AW(3),
Nakagawa T(4), Craig AM(2), Jones EY(1), Aricescu AR(1).

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.

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.

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

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