Structural basis for integration of GluD receptors within synaptic organizer complexes.

Elegheert J, Kakegawa W, Clay JE, Shanks NF, Behiels E, Matsuda K, Kohda K, Miura E, Rossmann M, Mitakidis N, Motohashi J, Chang VT, Siebold C, Greger IH, Nakagawa T, Yuzaki M, Aricescu AR
Science. 2016 353 (6296): 295-9

PMID: 27418511 · PMCID: PMC5291321 · DOI:10.1126/science.aae0104

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.

Copyright © 2016, American Association for the Advancement of Science.

MeSH Terms (13)

Animals Ligands Long-Term Synaptic Depression Mice Nerve Tissue Proteins Neurogenesis Protein Multimerization Protein Precursors Protein Structure, Tertiary Purkinje Cells Receptors, Glutamate Signal Transduction Synapses

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