TY  - JOUR
AU  - Coles, Charlotte H
AU  - Mitakidis, Nikolaos
AU  - Zhang, Peng
AU  - Elegheert, Jonathan
AU  - Lu, Weixian
AU  - Stoker, Andrew W
AU  - Nakagawa, Terunaga
AU  - Craig, Ann Marie
AU  - Jones, E Yvonne
AU  - Aricescu, A Radu
TI  - Structural basis for extracellular cis and trans RPTPσ signal competition in synaptogenesis.
JO  - Nature Communications
VL  - 5
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2020-07622
SP  - 5209
PY  - 2014
AB  - 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.
KW  - Animals
KW  - Cell Differentiation: physiology
KW  - Chick Embryo
KW  - Coculture Techniques
KW  - Crystallization
KW  - Extracellular Matrix Proteins: chemistry
KW  - Extracellular Matrix Proteins: physiology
KW  - Humans
KW  - Ligands
KW  - Mice
KW  - Neurogenesis: physiology
KW  - Neurons: cytology
KW  - Neurons: physiology
KW  - Protein Binding
KW  - Protein Structure, Tertiary
KW  - Proteoglycans: chemistry
KW  - Proteoglycans: physiology
KW  - Receptor, trkC: chemistry
KW  - Receptor, trkC: physiology
KW  - Receptor-Like Protein Tyrosine Phosphatases, Class 2: chemistry
KW  - Receptor-Like Protein Tyrosine Phosphatases, Class 2: physiology
KW  - Signal Transduction: physiology
KW  - Synapses: physiology
KW  - Extracellular Matrix Proteins (NLM Chemicals)
KW  - Ligands (NLM Chemicals)
KW  - Proteoglycans (NLM Chemicals)
KW  - Receptor, trkC (NLM Chemicals)
KW  - Receptor-Like Protein Tyrosine Phosphatases, Class 2 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25385546
C2  - pmc:PMC4239663
DO  - DOI:10.1038/ncomms6209
UR  - https://pub.dzne.de/record/141300
ER  -