2. Academic Validation
  3. Structural basis for integration of GluD receptors within synaptic organizer complexes

Structural basis for integration of GluD receptors within synaptic organizer complexes

  • Science. 2016 Jul 15;353(6296):295-9. doi: 10.1126/science.aae0104.
Jonathan Elegheert 1,  Wataru Kakegawa 2,  Jordan E Clay 1,  Natalie F Shanks 3,  Ester Behiels 1,  Keiko Matsuda 2,  Kazuhisa Kohda 2,  Eriko Miura 2,  Maxim Rossmann 4,  Nikolaos Mitakidis 1,  Junko Motohashi 2,  Veronica T Chang 1,  Christian Siebold 1,  Ingo H Greger 4,  Terunaga Nakagawa 3,  Michisuke Yuzaki 5,  A Radu Aricescu 6
Affiliations

Affiliations

  • 1 Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
  • 2 Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
  • 3 Department of Molecular Physiology and Biophysics, School of Medicine, Vanderbilt University, Nashville, TN 37232-0615, USA.
  • 4 Neurobiology Division, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
  • 5 Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. radu@strubi.ox.ac.uk myuzaki@a5.keio.jp.
  • 6 Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. radu@strubi.ox.ac.uk myuzaki@a5.keio.jp.
PMID: 27418511 DOI: 10.1126/science.aae0104
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.

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