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Kainate receptor modulation by NETO2

Author

Listed:
  • Lingli He

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Jiahui Sun

    (Nanjing University
    Nanjing University)

  • Yiwei Gao

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Bin Li

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yuhang Wang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yanli Dong

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Weidong An

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Hang Li

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Bei Yang

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yuhan Ge

    (Nanjing University
    Nanjing University)

  • Xuejun Cai Zhang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yun Stone Shi

    (Nanjing University
    Nanjing University
    Nanjing University
    Nanjing University)

  • Yan Zhao

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

Abstract

Glutamate-gated kainate receptors are ubiquitous in the central nervous system of vertebrates, mediate synaptic transmission at the postsynapse and modulate transmitter release at the presynapse1–7. In the brain, the trafficking, gating kinetics and pharmacology of kainate receptors are tightly regulated by neuropilin and tolloid-like (NETO) proteins8–11. Here we report cryo-electron microscopy structures of homotetrameric GluK2 in complex with NETO2 at inhibited and desensitized states, illustrating variable stoichiometry of GluK2–NETO2 complexes, with one or two NETO2 subunits associating with GluK2. We find that NETO2 accesses only two broad faces of kainate receptors, intermolecularly crosslinking the lower lobe of ATDA/C, the upper lobe of LBDB/D and the lower lobe of LBDA/C, illustrating how NETO2 regulates receptor-gating kinetics. The transmembrane helix of NETO2 is positioned proximal to the selectivity filter and competes with the amphiphilic H1 helix after M4 for interaction with an intracellular cap domain formed by the M1–M2 linkers of the receptor, revealing how rectification is regulated by NETO2.

Suggested Citation

  • Lingli He & Jiahui Sun & Yiwei Gao & Bin Li & Yuhang Wang & Yanli Dong & Weidong An & Hang Li & Bei Yang & Yuhan Ge & Xuejun Cai Zhang & Yun Stone Shi & Yan Zhao, 2021. "Kainate receptor modulation by NETO2," Nature, Nature, vol. 599(7884), pages 325-329, November.
    • Handle: RePEc:nat:nature:v:599:y:2021:i:7884:d:10.1038_s41586-021-03936-y
    DOI: 10.1038/s41586-021-03936-y
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    Cited by:

    1. Danyang Zhang & Remigijus Lape & Saher A. Shaikh & Bianka K. Kohegyi & Jake F. Watson & Ondrej Cais & Terunaga Nakagawa & Ingo H. Greger, 2023. "Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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