The cryo-EM structure of a pannexin 1 reveals unique motifs for ion selection and inhibition
- Cornell University, United States
- Cold Spring Harbor Laboratory, United States
Abstract
Pannexins are large-pore forming channels responsible for ATP release under a variety of physiological and pathological conditions. Although predicted to share similar membrane topology with other large-pore forming proteins such as connexins, innexins, and LRRC8, pannexins have minimal sequence similarity to these protein families. Here, we present the cryo-EM structure of a frog pannexin 1 (Panx1) channel at 3.0 Å. We find that Panx1 protomers harbor four transmembrane helices similar in arrangement to other large-pore forming proteins but assemble as a heptameric channel with a unique constriction formed by Trp74 in the first extracellular loop. Mutating Trp74 or the nearby Arg75 disrupt ion selectivity whereas altering residues in the hydrophobic groove formed by the two extracellular loops abrogates channel inhibition by carbenoxolone. Our structural and functional study establishes the extracellular loops as important structural motifs for ion selectivity and channel inhibition in Panx1.
Data availability
Cryo EM data and the pannexin model has been deposited in PDB under the accession code 6VD7.
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Cryo-EM structure of Xenopus tropicalis pannexin 1 channelProtein Data Bank (accession no: 6VD7).
Article and author information
Author details
Funding
National Institutes of Health (GM114379)
- Toshimitsu Kawate
National Institutes of Health (NS113632)
- Hiro Furukawa
National Institutes of Health (GM008267)
- Kevin Michalski
- Erik Henze
- Julia Kumpf
National Institutes of Health (GM008267)
- Kevin Michalski
Robertson funds at Cold Spring Harbor Laboratory
- Hiro Furukawa
Doug Fox Alzheimer's fund
- Hiro Furukawa
Austin's purpose
- Hiro Furukawa
Heartfelt Wing Alzheimer's fund
- Hiro Furukawa
Charles H Revson Foundation (Senior Fellowship in Biomedical Science)
- Johanna L Syrjanen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Michalski et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The cryo-EM structure of a pannexin 1 reveals unique motifs for ion selection and inhibition
eLife 9:e54670.
https://doi.org/10.7554/eLife.54670
