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Structures of human pannexin 1 reveal ion pathways and mechanism of gating

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journal contribution
posted on 12.03.2021, 23:52 by Zheng Ruan, Ian J. Orozco, Juan Du, Wei Lü
Pannexin 1 (PANX1) is an ATP-permeable channel with critical roles in a variety of
physiological functions such as blood pressure regulation 1 , apoptotic cell clearance 2
and human oocyte development 3 . Here we present several structures of human PANX1
in a heptameric assembly at resolutions of up to 2.8 angström, including an apo state,
a caspase-7-cleaved state and a carbenoxolone-bound state. We reveal a gating
mechanism that involves two ion-conducting pathways. Under normal cellular
conditions, the intracellular entry of the wide main pore is physically plugged by the
C-terminal tail. Small anions are conducted through narrow tunnels in the
intracellular domain. These tunnels connect to the main pore and are gated by a long
linker between the N-terminal helix and the first transmembrane helix. During
apoptosis, the C-terminal tail is cleaved by caspase, allowing the release of ATP
through the main pore. We identified a carbenoxolone-binding site embraced by W74
in the extracellular entrance and a role for carbenoxolone as a channel blocker. We
identified a gap-junction-like structure using a glycosylation-deficient mutant, N255A.
Our studies provide a solid foundation for understanding the molecular mechanisms
underlying the channel gating and inhibition of PANX1 and related large-pore
channels.

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20POST35120556

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