The Cryo-EM structure of pannexin 1 reveals unique motifs for ion selection and inhibition

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 sim...

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Bibliographic Details
Published in:eLife 2020-02, Vol.9
Main Authors: Michalski, Kevin, Syrjanen, Johanna L, Henze, Erik, Kumpf, Julia, Furukawa, Hiro, Kawate, Toshimitsu
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amino acids
Animals
ATP release
Binding sites
carbenoxolone
Carbenoxolone - pharmacology
Connexins
Connexins - antagonists & inhibitors
Connexins - chemistry
Connexins - metabolism
Connexins - ultrastructure
Cryoelectron Microscopy
Data collection
EDTA
extracellular loop
HEK293 Cells
heptameric channel
Humans
Hydrophobicity
ion selectivity
Kinases
Microscopy
Neuroscience
pannexin
Physiological aspects
Protein families
Protein Structure, Tertiary
Proteins
Structural Biology and Molecular Biophysics
Structure (Literature)
Structure-function relationships
Xenopus laevis
Xenopus Proteins - antagonists & inhibitors
Xenopus Proteins - chemistry
Xenopus Proteins - metabolism
Xenopus Proteins - ultrastructure
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Description
Summary: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.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.54670