Structural basis for proton inhibition of the two-pore domain K⁺ channel TASK-1

TASK-1 is a pH-sensitive two-pore domain K⁺ channel implicated in diseases including pulmonary arterial hypertension (PAH) and developmental delay with sleep apnea (DDSA). Structures of TASK-1 have been captured with an open external gate, but the structural basis for external proton inhibition is incompletely understood. Here, we present a cryo-EM structure of TASK-1 at pH 6.0 and 100 mM K⁺, revealing a closed extracellular gate. pH-regulation of TASK-1 involves a C-type selectivity filter gate similar to TASK-3, but distinct from other K2Ps, in which histidine protonation leads to the formation of a hydrophobic seal above the filter. We find that a PAH-associated loss-of-function mutation near the outer gate increases proton sensitivity, while DDSA-associated and other gain-of-function mutations near the inner X-gate and cavity reduce proton sensitivity. These data reveal the mechanism for pH regulation of TASK-1, illustrate differences in C-type gating among K2Ps, and suggest allosteric communication between inner and outer gates.