Inhibition of the proton-activated chloride channel PAC by PIP2
Author:
Mihaljević Ljubica1ORCID,
Ruan Zheng2ORCID,
Osei-Owusu James1,
Lü Wei2ORCID,
Qiu Zhaozhu13ORCID
Affiliation:
1. Department of Physiology, Johns Hopkins University School of Medicine
2. Department of Structural Biology, Van Andel Institute
3. Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine
Abstract
Proton-activated chloride (PAC) channel is a ubiquitously expressed pH-sensing ion channel, encoded by PACC1 (TMEM206). PAC regulates endosomal acidification and macropinosome shrinkage by releasing chloride from the organelle lumens. It is also found at the cell surface, where it is activated under pathological conditions related to acidosis and contributes to acid-induced cell death. However, the pharmacology of the PAC channel is poorly understood. Here, we report that phosphatidylinositol (4,5)-bisphosphate (PIP2) potently inhibits PAC channel activity. We solved the cryo-electron microscopy structure of PAC with PIP2 at pH 4.0 and identified its putative binding site, which, surprisingly, locates on the extracellular side of the transmembrane domain (TMD). While the overall conformation resembles the previously resolved PAC structure in the desensitized state, the TMD undergoes remodeling upon PIP2-binding. Structural and electrophysiological analyses suggest that PIP2 inhibits the PAC channel by stabilizing the channel in a desensitized-like conformation. Our findings identify PIP2 as a new pharmacological tool for the PAC channel and lay the foundation for future drug discovery targeting this channel.
Funder
Boehringer Ingelheim Fonds
National Institute of General Medical Sciences
American Heart Association
National Institutes of Health
McKnight Foundation
Alfred P. Sloan Foundation
Esther A. and Joseph Klingenstein Fund
Publisher
eLife Sciences Publications, Ltd
Subject
General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience
Cited by
1 articles.
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