6WLV

Structural basis for pH gating of the two-pore domain K + channel TASK2.

(2020) Nature 586: 457-462

• PubMed: 32999458 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1038/s41586-020-2770-2
• Primary Citation of Related Structures:  
  6WLV, 6WM0


• PubMed Abstract: 
  

  TASK2 (also known as KCNK5) channels generate pH-gated leak-type K ⁺ currents to control cellular electrical excitability ^1-3 . TASK2 is involved in the regulation of breathing by chemosensory neurons of the retrotrapezoid nucleus in the brainstem ^4-6 and pH homeostasis by kidney proximal tubule cells ^7,8 . These roles depend on channel activation by intracellular and extracellular alkalization ^3,8,9 , but the mechanistic basis for TASK2 gating by pH is unknown. Here we present cryo-electron microscopy structures of Mus musculus TASK2 in lipid nanodiscs in open and closed conformations. We identify two gates, distinct from previously observed K ⁺ channel gates, controlled by stimuli on either side of the membrane. Intracellular gating involves lysine protonation on inner helices and the formation of a protein seal between the cytoplasm and the channel. Extracellular gating involves arginine protonation on the channel surface and correlated conformational changes that displace the K ⁺ -selectivity filter to render it nonconductive. These results explain how internal and external protons control intracellular and selectivity filter gates to modulate TASK2 activity.

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Organizational Affiliation: 

Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA, USA.