TASK-1 and TASK-3 are pH-sensitive two-pore domain (K2P/KCNK) K⁺ channels. Their functional roles make them promising targets for treatment of multiple disorders including sleep apnea, pain, and atrial fibrillation. Mutations in these channels are also associated with neurodevelopmental and hypertensive disorders. A previous crystal structure of TASK-1 revealed a lower “X-gate” as a hotspot for missense gain-of-function (GoF) mutations associated with DDSA (developmental delay with sleep apnea). However, the mechanisms of gating in TASK channels are still not fully understood. Here, we resolve structures for both human TASK-1 and TASK-3 by cryoelectron microscopy (cryo-EM), as well as a recurrent TASK-3 variant (G236R) associated with KCNK9 imprinting syndrome (KIS) (formerly known as Birk-Barel syndrome). Combined with functional studies of the X-gating mechanism, we provide evidence for how a highly conserved gating mechanism becomes defective in disease, and also provide further insight into the pathway of conformational changes that underlie the pH-dependent inhibition of TASK channel activity.

中文翻译：

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TASK-1 和 TASK-3 K2P 通道的结构有助于深入了解它们在疾病中的门控和功能障碍


TASK-1 和 TASK-3 是 pH 敏感的双孔结构域 （K2P/KCNK） K⁺ 通道。它们的功能作用使它们成为治疗多种疾病（包括睡眠呼吸暂停、疼痛和心房颤动）的有希望的靶点。这些通道的突变也与神经发育和高血压疾病有关。TASK-1 的先前晶体结构显示，较低的“X 门”是与 DDSA（睡眠呼吸暂停伴发育迟缓）相关的错义功能获得 （GoF） 突变的热点。然而，TASK 通道中的门控机制仍未完全清楚。在这里，我们通过冷冻电子显微镜 （cryo-EM） 解析人类 TASK-1 和 TASK-3 的结构，以及与 KCNK9 印记综合征 （KIS） 相关的复发性 TASK-3 变体 （G236R）（以前称为 Birk-Barel 综合征）。结合 X 门控机制的功能研究，我们为高度保守的门控机制如何在疾病中变得缺陷提供了证据，并且还进一步了解了构成 TASK 通道活性 pH 依赖性抑制基础的构象变化途径。