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Published on: July 16, 2013
pH-dependent channel gating in connexin26 hemichannels involves conformational changes in N-terminus.
1Center of Bioinformatics, Northwest A&F University, Yangling, Shaanxi, 712100, China.
Biochimica Et Biophysica Acta
|January 31, 2012
Summary
Connexin (Cx) hemichannels regulate ion and metabolite exchange. Lowering pH protonates Asp2, opening the Cx26 channel, while neutral pH closes it via N-terminal helix interactions, controlling cell permeability.
Area of Science:
- Molecular biology
- Biophysics
- Cellular physiology
Background:
- Connexin (Cx) hemichannels facilitate intercellular communication by exchanging ions and metabolites.
- Intracellular pH variations influence hemichannel activity during physiological and pathological states.
- Understanding the precise mechanism of pH modulation on hemichannels is crucial for cellular regulation.
Purpose of the Study:
- To elucidate the molecular mechanism by which pH affects Cx26 hemichannel gating.
- To investigate the structural dynamics of Cx26 under acidic and neutral conditions using molecular dynamics simulations.
Main Methods:
- Performed two 100-ns molecular dynamics simulations of the Cx26 channel.
- Analyzed channel conformation, pore radius, and interactions under acidic and neutral pH conditions.
Main Results:
- Transmembrane domains exhibited clockwise motion; extracellular segments remained stable under both pH conditions.
- At neutral pH, Cx26 adopted a closed conformation stabilized by N-terminal helix interactions, with Asp2 acting as a gate (pore radius < 2Å).
- At acidic pH, Asp2 protonation disrupted interactions, leading to channel opening (pore radius > 4.5Å) and allowing chloride ion passage.
Conclusions:
- A pH-dependent gating mechanism for Cx26 hemichannels involving aspartic residue protonation was proposed.
- The study highlights the sophisticated role of pH sensitivity in regulating ion permeation through hemichannels.
- Asp2 and Lys41 residues play critical roles in the pH-mediated gating and ion interaction within the Cx26 channel.
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