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Structural basis for integration of GluD receptors within synaptic organizer complexes

DOI: 10.1126/science.aae0104 DOI Help

Authors: Jonathan Elegheert (Wellcome Trust Centre for Human Genetics, University of Oxford) , W. Kakegawa (Keio University School of Medicine) , J. Clay (University of Oxford) , N. F. Shanks (Vanderbilt University) , E. Behiels (Wellcome Trust Centre for Human Genetics, University of Oxford) , K. Matsuda (Keio University School of Medicine) , K. Kohda (Keio University School of Medicine) , E. Miura (Keio University School of Medicine) , M. Rossmann (MRC Laboratory of Molecular Biology) , Nikolaos Mitakidis (Wellcome Trust Centre for Human Genetics, University of Oxford) , J. Motohashi (Keio University School of Medicine) , Veronica T. Chang (Wellcome Trust Centre for Human Genetics, University of Oxford) , Christian Siebold (Wellcome Trust Centre for Huuman Genetics, University of Oxford) , Ingo H. Greger (MRC Laboratory of Molecular Biology) , Terunaga Nakagawa (Vanderbilt University) , M. Yuzaki (Keio University School of Medicine) , A. Radu Aricescu (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Science , VOL 353 , PAGES 295 - 299

State: Published (Approved)
Published: July 2016
Diamond Proposal Number(s): 8423 , 10627

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.

Subject Areas: Biology and Bio-materials

Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 29/09/2016 22:30

Discipline Tags:

Health & Wellbeing Neurology Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)