Structural basis of gating modulation of Kv4 channel complexes.
Structural basis of gating modulation of Kv4 channel complexes.
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DOI：
10.1038/s41586-021-03935-z
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发表时间：
2021-11
期刊：
影响因子：
64.8
通讯作者：
Nureki O
中科院分区：
文献类型：
--
作者：
Kise Y;Kasuya G;Okamoto HH;Yamanouchi D;Kobayashi K;Kusakizako T;Nishizawa T;Nakajo K;Nureki O
辅助亚基对电压门控钾（Kv）通道的调节是脑和心脏中通道生理功能的核心。天然Kv 4四聚体通道与两个辅助β亚基-细胞内Kv通道相互作用蛋白（KChIP）和跨膜二肽基肽酶相关蛋白（DPP）-形成大分子三元复合物，以引起快速激活和失活A型电流，从而阻止动作电位的反向传播。然而，Kv 4通道复合物的调节机制在很大程度上仍然未知。在这里，我们报告的Kv4.2-DPP 6S-KChIP 1十二聚体复合物，Kv4.2-KChIP 1和Kv4.2-DPP 6S八聚体复合物，和Kv4.2单独的冷冻电子显微镜结构。Kv4.2-KChIP 1复合物的结构揭示了Kv4.2的细胞内N末端与其C末端相互作用，所述C末端从相邻Kv4.2亚基的S6门控螺旋延伸。KChIP 1捕获Kv4.2的N和C末端。因此，KChIP 1将防止N型失活并稳定S6构象以调节四聚体内S6螺旋的门控。相比之下，与报道的电压门控通道复合物的辅助亚基不同，DPP 6S与Kv4.2电压敏感结构域的S1和S2螺旋相互作用，这表明DPP 6S稳定S1-S2螺旋的构象。因此，DPP 6S可以加速S4螺旋的电压依赖性运动。KChIP 1和DPP 6S在Kv4.2-KChIP 1-DPP 6S三元复合物中不直接相互作用。因此，我们的数据表明，两种不同的调制模式有助于在一个添加剂的方式来唤起A型电流从本地Kv 4大分子复合物。电压门控钾通道Kv4.2单独和与辅助亚基（DPP 6S和/或KChIP 1）复合的冷冻电子显微镜结构揭示了这两种不同亚基在调节通道活性中的不同机制。
Modulation of voltage-gated potassium (Kv) channels by auxiliary subunits is central to the physiological function of channels in the brain and heart. Native Kv4 tetrameric channels form macromolecular ternary complexes with two auxiliary β-subunits—intracellular Kv channel-interacting proteins (KChIPs) and transmembrane dipeptidyl peptidase-related proteins (DPPs)—to evoke rapidly activating and inactivating A-type currents, which prevent the backpropagation of action potentials. However, the modulatory mechanisms of Kv4 channel complexes remain largely unknown. Here we report cryo-electron microscopy structures of the Kv4.2–DPP6S–KChIP1 dodecamer complex, the Kv4.2–KChIP1 and Kv4.2–DPP6S octamer complexes, and Kv4.2 alone. The structure of the Kv4.2–KChIP1 complex reveals that the intracellular N terminus of Kv4.2 interacts with its C terminus that extends from the S6 gating helix of the neighbouring Kv4.2 subunit. KChIP1 captures both the N and the C terminus of Kv4.2. In consequence, KChIP1 would prevent N-type inactivation and stabilize the S6 conformation to modulate gating of the S6 helices within the tetramer. By contrast, unlike the reported auxiliary subunits of voltage-gated channel complexes, DPP6S interacts with the S1 and S2 helices of the Kv4.2 voltage-sensing domain, which suggests that DPP6S stabilizes the conformation of the S1–S2 helices. DPP6S may therefore accelerate the voltage-dependent movement of the S4 helices. KChIP1 and DPP6S do not directly interact with each other in the Kv4.2–KChIP1–DPP6S ternary complex. Thus, our data suggest that two distinct modes of modulation contribute in an additive manner to evoke A-type currents from the native Kv4 macromolecular complex. Cryo-electron microscopy structures of the voltage-gated potassium channel Kv4.2 alone and in complex with auxiliary subunits (DPP6S and/or KChIP1) reveal the distinct mechanisms of these two different subunits in modulating channel activity.
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