1. Kainate receptor modulation by NETO2
- Author
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He, Lingli, Sun, Jiahui, Gao, Yiwei, Li, Bin, Wang, Yuhang, Dong, Yanli, An, Weidong, Li, Hang, Yang, Bei, Ge, Yuhan, Zhang, Xuejun Cai, Shi, Yun Stone, and Zhao, Yan
- Subjects
Quantitative Biology - Biomolecules - Abstract
Glutamate-gated kainate receptors (KARs) are ubiquitous in the central nervous system of vertebrates, mediate synaptic transmission on post-synapse, and modulate transmitter release on pre-synapse. In the brain, the trafficking, gating kinetics, and pharmacology of KARs are tightly regulated by Neuropilin and tolloid-like proteins (Netos). Here we report cryo-EM structures of homo-tetrameric GluK2 in complex with Neto2 at inhibited and desensitized states, illustrating variable stoichiometry of GluK2-Neto2 complexes, with one or two Neto2 subunits associate with the GluK2. We find that Neto2 accesses only two broad faces of KARs, intermolecularly crosslinking the lower-lobe of ATDA/C, upper-lobe of LBDB/D, and 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 interacting with an ICD formed by the M1-M2 linkers of the receptor, revealing how rectification is regulated by Neto2.
- Published
- 2023
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