title: Structural basis for integration of GluD receptors within synaptic organizer complexes.
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.
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Elegheert
authors.affiliation: Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Kakegawa
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Jordan E
authors.initials: JE
authors.lastname: Clay
authors.affiliation: Department of Molecular Physiology and Biophysics, School of Medicine, Vanderbilt University, Nashville, TN 37232-0615, USA.
authors.forename: Natalie F
authors.initials: NF
authors.lastname: Shanks
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Ester
authors.initials: E
authors.lastname: Behiels
authors.affiliation: Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Matsuda
authors.affiliation: Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Kohda
authors.affiliation: Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Miura
authors.affiliation: Neurobiology Division, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Maxim
authors.initials: M
authors.lastname: Rossmann
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Mitakidis
authors.affiliation: Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Motohashi
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Veronica T
authors.initials: VT
authors.lastname: Chang
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Siebold
authors.affiliation: Neurobiology Division, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Ingo H
authors.initials: IH
authors.lastname: Greger
authors.affiliation: Department of Molecular Physiology and Biophysics, School of Medicine, Vanderbilt University, Nashville, TN 37232-0615, USA.
authors.forename: Terunaga
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: 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.
authors.forename: Michisuke
authors.initials: M
authors.lastname: Yuzaki
authors.affiliation: 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.
authors.forename: A Radu
authors.initials: AR
authors.lastname: Aricescu
mesh_terms: D000818:Animals; D008024:Ligands; D036881:Long-Term Synaptic Depression; D051379:Mice; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D055495:Neurogenesis; D055503:Protein Multimerization; D011498:Protein Precursors / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011689:Purkinje Cells / Q000378:metabolism / Q000502:physiology; D017470:Receptors, Glutamate / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism / Q000502:physiology*
chemical_list: C092370:Cbln1 protein, mouse; D008024:Ligands; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; D017470:Receptors, Glutamate; C107913:glutamate receptor delta 2; C086959:neurexin Ibeta