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The C-terminal activating domain promotes Panx1 channel opening
Erik Henze1, Jacqueline J Ehrlich1, Janice L Robertson2
1Department of Molecular Medicine, Cornell University, Ithaca, NY 14853, USA.
Biorxiv : the Preprint Server for Biology
|June 25, 2024
Summary
Pannexin 1 (Panx1) channel activation involves a C-terminal activating domain (CAD) that repositions the N-terminus. This movement alters the pore
Area of Science:
- Cellular Biology
- Ion Channel Physiology
- Biophysics
Background:
- Pannexin 1 (Panx1) channels release ATP from apoptotic cells.
- Caspase cleavage of Panx1's C-terminus is known to open the channel.
Purpose of the Study:
- Investigate the mechanism of Panx1 channel activation beyond simple C-terminal cleavage.
- Identify novel domains and conformational changes regulating Panx1 channel function.
Main Methods:
- Site-directed mutagenesis
- Electrophysiology
- Cryo-electron microscopy (Cryo-EM)
- Electrostatic free energy landscape analysis
Main Results:
- A C-terminal activating domain (CAD) is crucial for Panx1 activation.
- Two conserved leucine residues in the CAD are essential for its function.
- Cryo-EM revealed that the CAD occupies an intracellular pocket, repositioning the N-terminus.
- N-terminus repositioning alters the pore's electrostatic landscape, reducing anion accumulation.
Conclusions:
- Panx1 activation involves a novel mechanism where CAD cleavage and repositioning of the N-terminus regulate channel gating.
- The dynamic changes in the electrostatic landscape of the pore influence ion permeation selectivity.
- This study elucidates a new model for Panx1 channel regulation.
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