Kainate receptor modulation by NETO2
Kainate receptor modulation by NETO2
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DOI：
10.1038/s41586-021-03936-y
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发表时间：
2021-09-22
期刊：
影响因子：
64.8
通讯作者：
Zhao, Yan
中科院分区：
文献类型：
--
作者：
He, Lingli;Sun, Jiahui;Zhao, Yan
谷氨酸门控盐酸盐受体普遍存在于脊椎动物的中枢神经系统中，在突触后介导突触传递，并在突触前调节递质释放（1-7）。在大脑中，海碱盐受体的转运、门控动力学和药理学受到神经肽和脂质样蛋白（NETO）的严格调控（8-11）。在这里，我们报道了同四聚体GluK2与NETO2复合物在抑制和脱敏状态下的低温电镜结构，说明了GluK2-NETO2复合物的可变化学统计，其中一个或两个NETO2亚基与GluK2相关。我们发现NETO2仅能通过ATD的下叶（A/C）、LBDB/D的上叶和LBDA/C的下叶进行分子间交联，说明了NETO2是如何调节受体门控动力学的。NETO2的跨膜螺旋位于选择性过滤器附近，并与M4后的两亲性H1螺旋竞争，与由受体M1-M2连接体形成的细胞内帽结构域相互作用，揭示了NETO2如何调节纠正。
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 presynapse(1-7). In the brain, the trafficking, gating kinetics and pharmacology of kainate receptors are tightly regulated by neuropilin and tolloid-like (NETO) proteins(8-11). 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 ATD(A/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.