Voltage-dependent conformational changes in connexin channels.

Area of Science:

• Biophysics
• Structural Biology
• Molecular Biology

Background:

• Connexin channels mediate cell-to-cell communication and possess voltage-dependent gating.
• Two gating mechanisms, fast (V(j)-gating) and slow (loop-gating), have been identified.
• Understanding the closed-state conformations is crucial for elucidating channel function.

Purpose of the Study:

• To identify structural constraints for the loop-gate closed state of connexin channels.
• To investigate the distinct mechanisms underlying V(j)-gating in different connexin subtypes.
• To integrate experimental and computational data for modeling connexin channel gating.

Main Methods:

• Metal bridge formation and chemical cross-linking to probe the channel pore.
• Analysis of X-ray crystal structures and electron crystallographic data.
• Molecular dynamics (MD) simulations and thermodynamic modeling.

Main Results:

• Identified a pore region contributing to the loop-gate permeability barrier with significant conformational changes.
• Observed large reductions in channel pore diameter during loop-gating.
• Proposed distinct V(j)-gating mechanisms involving N-terminal or C-terminal domains, with potential links to pH gating.

Conclusions:

• Provided positional constraints for modeling the loop-gate closed state.
• Highlighted the complexity and potential diversity of V(j)-gating mechanisms across connexin channels.
• Emphasized the integration of experimental and computational approaches to understand allosteric transitions in channel gating.