Structural basis for extracellular cis and trans RPTPσ signal competition in synaptogenesis
| Autor: | 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 |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Neurogenesis
chemistry [Extracellular Matrix Proteins] physiology [Proteoglycans] Chick Embryo Ligands Article physiology [Extracellular Matrix Proteins] Mice physiology [Signal Transduction] Animals Humans physiology [Receptor trkC] Receptor trkC Neurons Extracellular Matrix Proteins physiology [Receptor-Like Protein Tyrosine Phosphatases Class 2] Receptor-Like Protein Tyrosine Phosphatases Class 2 Cell Differentiation physiology [Neurogenesis] physiology [Neurons] Coculture Techniques Protein Structure Tertiary chemistry [Receptor trkC] chemistry [Proteoglycans] physiology [Cell Differentiation] nervous system Synapses cytology [Neurons] Proteoglycans ddc:500 chemistry [Receptor-Like Protein Tyrosine Phosphatases Class 2] physiology [Synapses] Crystallization Signal Transduction Protein Binding |
| Zdroj: | Nature Communications 5(1), 5209 (2014). doi:10.1038/ncomms6209 'Nature Communications ', vol: 5, pages: 5209-1-5209-12 (2014) Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/ncomms6209 |
| Popis: | 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. Receptor protein tyrosine phosphatase sigma (RPTPσ) promotes both neurite outgrowth and synaptic organization. Here, Coles et al. present the structural basis for this switch in function, whereby TrkC on the postsynaptic membrane and heparan sulphate proteoglycans compete for the same binding surface on RPTPσ. |
| Databáze: | OpenAIRE |
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