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

doi:10.1126/science.aae0104

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	295-300
Number of pages	6
Journal	Science
Volume	353
Issue number	6296
DOIs	https://doi.org/10.1126/science.aae0104
Publication status	Published - 2016 Jul 15
Externally published	Yes

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Elegheert, J., Kakegawa, W., Clay, J. E., Shanks, N. F., Behiels, E., Matsuda, K., Kohda, K., Miura, E., Rossmann, M., Mitakidis, N., Motohashi, J., Chang, V. T., Siebold, C., Greger, I. H., Nakagawa, T., Yuzaki, M., & Aricescu, A. R. (2016). Structural basis for integration of GluD receptors within synaptic organizer complexes. Science, 353(6296), 295-300. https://doi.org/10.1126/science.aae0104

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 2016, 'Structural basis for integration of GluD receptors within synaptic organizer complexes', Science, vol. 353, no. 6296, pp. 295-300. https://doi.org/10.1126/science.aae0104

@article{88aa8823b5f441fbbb4ac6ba96b4af86,

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.",

author = "Jonathan Elegheert and Wataru Kakegawa and Clay, {Jordan E.} and Shanks, {Natalie F.} and Ester Behiels and Keiko Matsuda and Kazuhisa Kohda and Eriko Miura and Maxim Rossmann and Nikolaos Mitakidis and Junko Motohashi and Chang, {Veronica T.} and Christian Siebold and Greger, {Ingo H.} and Terunaga Nakagawa and Michisuke Yuzaki and Aricescu, {A. Radu}",

note = "Funding Information: We thank staff at Diamond Light Source, T. Walter and K. Harlos for crystallization technical support, N. Scull for assistance with molecular biology, and E.Y. Jones and P. Miller for comments on the manuscript. This work was funded by the UK Medical Research Council (MRC) (G0700232 and L009609 to A.R.A. and MC-U105174197 to I.H.G.), the Japan Society for the Promotion of Science (15H05772 to M.Y. and 26117515, 26293042 to W.K.), the Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (to M.Y.), the Takeda Science Foundation (W.K. and M.Y.), the Yamada Science Foundation (W.K.), the Human Frontier Science Program (RGP0065/2014 to M.Y. and A.R.A.), and the NIH (R01HD061543 to T.N.). The Wellcome Trust Centre for Human Genetics is supported by Wellcome Trust grant 090532/Z/09/Z. J.E. was supported by European Molecular Biology Organization (ALTF 1116-2012) and Marie-Curie (FP7-328531) fellowships, C.S. is a Cancer Research UK senior research fellow (C20724/A14414), and A.R.A. is an MRC senior research fellow (MR/L009609/1). Structure factors and coordinates of Cbln1C1q, Cbln1DVRSG crystal forms 1 and 2, GluD2ATD, GluD1ATD, and Cbln1C1q-GluD2ATD are deposited in the Protein Data Bank (PDB codes 5KC5, 5KC6, 5KC7, 5KC8, 5KC9 and 5KCA, respectively).",

year = "2016",

month = jul,

day = "15",

doi = "10.1126/science.aae0104",

language = "English",

volume = "353",

pages = "295--300",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6296",

}

TY - JOUR

T1 - Structural basis for integration of GluD receptors within synaptic organizer complexes

AU - Elegheert, Jonathan

AU - Kakegawa, Wataru

AU - Clay, Jordan E.

AU - Shanks, Natalie F.

AU - Behiels, Ester

AU - Matsuda, Keiko

AU - Kohda, Kazuhisa

AU - Miura, Eriko

AU - Rossmann, Maxim

AU - Mitakidis, Nikolaos

AU - Motohashi, Junko

AU - Chang, Veronica T.

AU - Siebold, Christian

AU - Greger, Ingo H.

AU - Nakagawa, Terunaga

AU - Yuzaki, Michisuke

AU - Aricescu, A. Radu

N1 - Funding Information: We thank staff at Diamond Light Source, T. Walter and K. Harlos for crystallization technical support, N. Scull for assistance with molecular biology, and E.Y. Jones and P. Miller for comments on the manuscript. This work was funded by the UK Medical Research Council (MRC) (G0700232 and L009609 to A.R.A. and MC-U105174197 to I.H.G.), the Japan Society for the Promotion of Science (15H05772 to M.Y. and 26117515, 26293042 to W.K.), the Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (to M.Y.), the Takeda Science Foundation (W.K. and M.Y.), the Yamada Science Foundation (W.K.), the Human Frontier Science Program (RGP0065/2014 to M.Y. and A.R.A.), and the NIH (R01HD061543 to T.N.). The Wellcome Trust Centre for Human Genetics is supported by Wellcome Trust grant 090532/Z/09/Z. J.E. was supported by European Molecular Biology Organization (ALTF 1116-2012) and Marie-Curie (FP7-328531) fellowships, C.S. is a Cancer Research UK senior research fellow (C20724/A14414), and A.R.A. is an MRC senior research fellow (MR/L009609/1). Structure factors and coordinates of Cbln1C1q, Cbln1DVRSG crystal forms 1 and 2, GluD2ATD, GluD1ATD, and Cbln1C1q-GluD2ATD are deposited in the Protein Data Bank (PDB codes 5KC5, 5KC6, 5KC7, 5KC8, 5KC9 and 5KCA, respectively).

PY - 2016/7/15

Y1 - 2016/7/15

N2 - 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.

AB - 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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U2 - 10.1126/science.aae0104

DO - 10.1126/science.aae0104

M3 - Article

C2 - 27418511

AN - SCOPUS:84978372349

SN - 0036-8075

VL - 353

SP - 295

EP - 300

JO - Science

JF - Science

IS - 6296

ER -

Structural basis for integration of GluD receptors within synaptic organizer complexes

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