Should I Stick Or Should I Go? A molecular switch at the neuronal surface

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• Radu Aricescu, University of Oxford
• Tuesday 22 April 2014, 14:00-15:00
• MRC LMB: Sanger Seminar Room 3A180.

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Receptor protein tyrosine phosphatase sigma (RPTPσ), which regulates neuronal extension through interactions with proteoglycans, has recently emerged as a presynaptic nexus for multiple protein and proteoglycan interactions during synaptogenesis. Mechanisms governing the shift in RPTP σ function from outgrowth promotion and its subsequent ability to act as a synaptic organizer are unknown. Crystallographic and electron microscopic analyses of the RPTP σ ectodomain reveal an extensive inter-domain flexibility. Furthermore, a crystal structure of RPTP σ in complex with the postsynaptic receptor protein tyrosine kinase TrkC details an interaction surface partially overlapping the previously characterized proteoglycan-binding site suggesting competition between presynaptic proteoglycans and postsynaptic TrkC. Accordingly, heparin oligomers inhibit RPTP σ:TrkC interaction in vitro and disrupt TrkC-dependent synaptic differentiation. Various lines of evidence converge towards a model whereby transient emergence of the RPTP σ ectodomain from the presynaptic proteoglycan layer allows capture by TrkC to form a trans-synaptic complex, the consequent reduction in RPTP σ flexibility potentiating interactions with additional postsynaptic ligands to orchestrate excitatory synapse formation.

This talk is part of the MRC LMB Neurobiology Seminars series.

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