Structural basis for integration of GluD receptors within synaptic organizer complexes

Jonathan Elegheert, Wataru Kakegawa, Jordan E. Clay, Natalie F. Shanks, Ester Behiels, Keiko Matsuda, Kazuhisa Kohda, Eriko Miura, Maxim Rossmann, Nikolaos Mitakidis, Junko Motohashi, Veronica T. Chang, Christian Siebold, Ingo H. Greger, Terunaga Nakagawa, Michisuke Yuzaki, A. Radu Aricescu

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Ionotropic glutamate receptor (iGluR) family members are integrated into supramolecular complexes that modulate their location and function at excitatory synapses. However, a lack of structural information beyond isolated receptors or fragments thereof currently limits the mechanistic understanding of physiological iGluR signaling. Here, we report structural and functional analyses of the prototypical molecular bridge linking postsynaptic iGluR δ2 (GluD2) and presynaptic β-neurexin 1 (β-NRX1) via Cbln1, a C1q-like synaptic organizer. We show how Cbln1 hexamers "anchor" GluD2 amino-terminal domain dimers to monomeric β-NRX1. This arrangement promotes synaptogenesis and is essential for D-serine-dependent GluD2 signaling in vivo, which underlies long-term depression of cerebellar parallel fiber-Purkinje cell (PF-PC) synapses and motor coordination in developing mice. These results lead to a model where protein and small-molecule ligands synergistically control synaptic iGluR function.

Original languageEnglish
Pages (from-to)295-300
Number of pages6
JournalScience
Volume353
Issue number6296
DOIs
Publication statusPublished - 2016 Jul 15

ASJC Scopus subject areas

  • General

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    Elegheert, J., Kakegawa, W., Clay, J. E., Shanks, N. F., Behiels, E., Matsuda, K., Kohda, K., Miura, E., Rossmann, M., Mitakidis, N., Motohashi, J., Chang, V. T., Siebold, C., Greger, I. H., Nakagawa, T., Yuzaki, M., & Aricescu, A. R. (2016). Structural basis for integration of GluD receptors within synaptic organizer complexes. Science, 353(6296), 295-300. https://doi.org/10.1126/science.aae0104