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
Science. 2016-07-14; 353(6296): 295-299
DOI: 10.1126/science.aae0104

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1. Science. 2016 Jul 15;353(6296):295-9. doi: 10.1126/science.aae0104.

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

Elegheert J(1), Kakegawa W(2), Clay JE(1), Shanks NF(3), Behiels E(1), Matsuda
K(2), Kohda K(2), Miura E(2), Rossmann M(4), Mitakidis N(1), Motohashi J(2),
Chang VT(1), Siebold C(1), Greger IH(4), Nakagawa T(3), Yuzaki M(5), Aricescu
AR(6).

Author information:
(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. .
(6)Division of Structural Biology, Wellcome Trust Centre for Human Genetics,
University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
.

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.

DOI: 10.1126/science.aae0104
PMCID: PMC5291321
PMID: 27418511 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus