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Electric field-induced pore constriction in the human Kv2.1 channel
Venkata Shiva Mandala1, Roderick MacKinnon1
1Laboratory of Molecular Neurobiology and Biophysics, HHMI, The Rockefeller University, New York, NY 10065.
Summary
Voltage-dependent ion channel gating involves voltage-sensing domains (VSDs) that shift the S4 helix. This movement alters pore conformation, opening or closing the channel based on VSD activation.
Area of Science:
- Molecular biology
- Biophysics
- Neuroscience
Background:
- Voltage-dependent ion channels control cellular excitability via transmembrane voltage.
- Voltage-sensing domains (VSDs) within these channels translate voltage changes into conformational alterations.
- The S4 transmembrane helix is a key component of VSDs, mediating voltage-dependent gating.
Purpose of the Study:
- To elucidate the structural mechanisms of voltage-dependent gating in the Kv2.1 channel.
- To investigate the conformational changes in Kv2.1 VSDs under varying transmembrane voltages.
- To compare the gating mechanisms of Kv2.1 and EAG1 channels.
Main Methods:
- Cryogenic electron microscopy (cryo-EM) was employed to visualize Kv2.1 structure.
- Kv2.1 channels were studied in lipid vesicles under different transmembrane voltage conditions.
- Structural analysis focused on the S4 helix movement and its impact on the pore domain.
Main Results:
- Hyperpolarization induced a ~5 Å displacement of the Kv2.1 S4 helix by one helical turn.
- Changes in S4 helix-pore interactions were observed, correlating with channel gating.
- Pore constriction occurred when all four VSDs exhibited S4 helix displacement, squeezing the S6 helices.
Conclusions:
- The Kv2.1 S4 helix displacement directly gates the ion channel pore.
- Partial VSD activation leaves the pore open, while full activation leads to constriction.
- Despite distinct architectures, Kv2.1 and EAG1 channels share similar voltage-sensing gating mechanisms.
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