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Kainate receptor modulation by NETO2
Nature ( IF 64.8 ) Pub Date : 2021-09-22 , DOI: 10.1038/s41586-021-03936-y
Lingli He 1, 2, 3 , Jiahui Sun 4, 5 , Yiwei Gao 1, 3 , Bin Li 1, 3 , Yuhang Wang 1, 3 , Yanli Dong 1, 2, 3 , Weidong An 1, 3 , Hang Li 1, 3 , Bei Yang 1, 2, 3 , Yuhan Ge 4, 5 , Xuejun Cai Zhang 1, 3 , Yun Stone Shi 4, 5, 6, 7 , Yan Zhao 1, 2, 3
Affiliation  

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 presynapse1,2,3,4,5,6,7. In the brain, the trafficking, gating kinetics and pharmacology of kainate receptors are tightly regulated by neuropilin and tolloid-like (NETO) proteins8,9,10,11. 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.



中文翻译:

NETO2 对红藻氨酸受体的调节

谷氨酸门控红藻氨酸受体普遍存在于脊椎动物的中枢神经系统中,介导突触后的突触传递并调节突触前的递质释放1,2,3,4,5,6,7。在大脑中,红藻氨酸受体的运输、门控动力学和药理学受到神经毡蛋白和类 tolloid (NETO) 蛋白8,9,10,11的严格调节。在这里,我们报告了在抑制和脱敏状态下与 NETO2 复合的同四聚体 GluK2 的冷冻电子显微镜结构,说明了 GluK2-NETO2 复合物的可变化学计量,其中一个或两个 NETO2 亚基与 GluK2 相关。我们发现 NETO2 仅访问红藻氨酸受体的两个宽面,分子间交联 ATD A/C的下叶, LBD B/D的上叶和 LBD A/C的下叶,说明 NETO2 如何调节受体门控动力学。NETO2 的跨膜螺旋位于选择性过滤器的近端,并在 M4 之后与两亲性 H1 螺旋竞争,与受体的 M1-M2 接头形成的细胞内帽结构域相互作用,揭示了 NETO2 是如何调节整流的。

更新日期:2021-09-22
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