Structure of the full-length human Pannexin1 channel and insights into its role in pyroptosis

Pannexin1 (PANX1) is a large-pore ATP efflux channel with a broad distribution, which allows the exchange of molecules and ions smaller than 1 kDa between the cytoplasm and extracellular space. In this study, we show that in human macrophages PANX1 expression is upregulated by diverse stimuli that promote pyroptosis, which is reminiscent of the previously reported lipopolysaccharide-induced upregulation of PANX1 during inflammasome activation. To further elucidate the function of PANX1, we propose the full-length human Pannexin1 (hPANX1) model through cryo-electron microscopy (cryo-EM) and molecular dynamics (MD) simulation studies, establishing hPANX1 as a homo-heptamer and revealing that both the N-termini and C-termini protrude deeply into the channel pore funnel. MD simulations also elucidate key energetic features governing the channel that lay a foundation to understand the channel gating mechanism. Structural analyses, functional characterizations, and computational studies support the current hPANX1-MD model, suggesting the potential role of hPANX1 in pyroptosis during immune responses.

Automated summary

The expression of PANX1 is upregulated by various stimuli in human macrophages that promote pyroptosis, with structural and functional studies revealing its potential role in pyroptosis during immune responses. Cryo-electron microscopy and molecular dynamics simulations support the model of hPANX1 as a homo-heptamer with N-termini and C-termini extending deep into the channel pore funnel, providing insights into the channel gating mechanism.