National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
R56HL144929
United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
R01NS111031
United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
R01NS112363
United States
American Heart Association
20POST35120556
United States
Citation
Journal: Nature / Year: 2020 Title: Structures and pH-sensing mechanism of the proton-activated chloride channel. Authors: Zheng Ruan / James Osei-Owusu / Juan Du / Zhaozhu Qiu / Wei Lü / Abstract: The proton-activated chloride channel (PAC) is active across a wide range of mammalian cells and is involved in acid-induced cell death and tissue injury. PAC has recently been shown to represent a ...The proton-activated chloride channel (PAC) is active across a wide range of mammalian cells and is involved in acid-induced cell death and tissue injury. PAC has recently been shown to represent a novel and evolutionarily conserved protein family. Here we present two cryo-electron microscopy structures of human PAC in a high-pH resting closed state and a low-pH proton-bound non-conducting state. PAC is a trimer in which each subunit consists of a transmembrane domain (TMD), which is formed of two helices (TM1 and TM2), and an extracellular domain (ECD). Upon a decrease of pH from 8 to 4, we observed marked conformational changes in the ECD-TMD interface and the TMD. The rearrangement of the ECD-TMD interface is characterized by the movement of the histidine 98 residue, which is, after acidification, decoupled from the resting position and inserted into an acidic pocket that is about 5 Å away. Within the TMD, TM1 undergoes a rotational movement, switching its interaction partner from its cognate TM2 to the adjacent TM2. The anion selectivity of PAC is determined by the positively charged lysine 319 residue on TM2, and replacing lysine 319 with a glutamate residue converts PAC to a cation-selective channel. Our data provide a glimpse of the molecular assembly of PAC, and a basis for understanding the mechanism of proton-dependent activation.
History
Deposition
Aug 4, 2020
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Header (metadata) release
Nov 11, 2020
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Map release
Nov 11, 2020
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Update
Dec 23, 2020
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Current status
Dec 23, 2020
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average exposure time: 8.0 sec. / Average electron dose: 49.6 e/Å2
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
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