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

Abstract

TASK-1 is a pH-sensitive two-pore domain K+ channel inhibited by external protons. TASK-1 is widely expressed, including in cardiomyocytes and chemosensitive neurons in the brain. Altered channel expression and activity are implicated in diseases including atrial fibrillation, pulmonary arterial hypertension, and developmental delay with sleep apnea. Structures of TASK-1 have been captured with an open external and closed internal gate. The structural basis for external proton inhibition and potential for communication between inner and outer gates are incompletely understood. Here, we determine a cryo-EM structure of TASK-1 at low pH with a closed extracellular gate and assess pH sensitivity of mutated channels. Proton inhibition of TASK-1 involves a C-type selectivity filter gate similar to TASK-3, but distinct from other proton-inhibited K2Ps TASK-2 and TWIK-1. Protonation of an extracellular histidine leads to formation of a hydrophobic seal above the selectivity filter and dilation of the outer two K+ coordination sites to close the channel pore. We find that a pulmonary arterial hypertension-associated loss-of-function mutation near the outer gate increases proton sensitivity, while gain-of-function mutations near the inner X-gate and intracellular cavity reduce proton sensitivity. These data reveal the structural basis for extracellular pH-gating of TASK-1, suggest allosteric communication between the inner and outer gates, and illustrate differences in C-type gating among related K+ channels.