Gating choreography and mechanism of the human proton-activated chloride channel $\mathrm{ASOR}$

Wang, Chongyuan; Polovitskaya, Maya M.; Delgado, Bryce D.; Jentsch, Thomas J.; Long, Stephen B.

doi:10.1126/sciadv.abm3942

Title: Gating choreography and mechanism of the human proton-activated chloride channel $$\mathrm{ASOR}$$

Journal Article · 01 February 2022 · Science Advances

DOI: https://doi.org/10.1126/sciadv.abm3942 · OSTI ID:1903923

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Memorial Sloan Kettering Cancer Center, New York, NY (United States); OSTI
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin (Germany)
Memorial Sloan Kettering Cancer Center, New York, NY (United States); Weill Cornell Medicine Graduate School of Medical Sciences, New York, NY (United States)
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin (Germany); Charité Universitätsmedizin, Berlin (Germany)
Memorial Sloan Kettering Cancer Center, New York, NY (United States)

The proton-activated chloride channel ASOR (TMEM206/PAC) permeates anions across cellular membranes in response to acidification, thereby enhancing acid-induced cell death and regulating endocytosis. The molecular mechanisms of pH-dependent control are not understood, in part because structural information for an activated conformation of ASOR is lacking. Here, we reconstitute function from purified protein and present a 3.1-Å-resolution cryo–electron microscopy structure of human ASOR at acidic pH in an activated conformation. The work contextualizes a previous acidic pH structure as a desensitized conformation. Combined with electrophysiological studies and high-resolution structures of resting and desensitized states, the work reveals mechanisms of proton sensing and ion pore gating. Clusters of extracellular acidic residues function as pH sensors and coalesce when protonated. Ensuing conformational changes induce metamorphosis of transmembrane helices to fashion an ion conduction pathway unique to the activated conformation. The studies identify a new paradigm of channel gating in this ubiquitous ion channel.

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Research Organization:: Memorial Sloan Kettering Cancer Center, New York, NY (United States)

Sponsoring Organization:: Dorris J. Hutchison Graduate Fellowship; European Research Council; German Research Foundation (DFG); National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 1903923

Journal Information:: Science Advances, Journal Name: Science Advances Journal Issue: 5 Vol. 8; ISSN 2375-2548

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: English

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