Eukaryotic Kv channel Shaker inactivates through selectivity filter dilation rather than collapse

Area of Science:

• Molecular biology
• Structural biology
• Biophysics

Background:

• Eukaryotic voltage-gated K+ channels are crucial for neuronal signaling.
• C-type inactivation is a key regulatory mechanism, but its structural basis is unclear.

Purpose of the Study:

• To determine the atomic structure of wild-type K+ channels in the C-type inactivated state.
• To elucidate the molecular mechanism underlying K+ channel C-type inactivation.

Main Methods:

• Atomic-resolution cryo-electron microscopy (cryo-EM) of wild-type Shaker K+ channels.
• All-atom molecular dynamics simulations.

Main Results:

• Cryo-EM revealed a dilated selectivity filter in the wild-type channel, consistent with C-type inactivation.
• Simulations confirmed this conformation explains residual ion conductance and altered ion selectivity.
• Simulations also rationalized the effects of mutations on inactivation rates.

Conclusions:

• The study establishes the molecular basis of C-type inactivation in eukaryotic K+ channels.
• The dilated selectivity filter is the structural hallmark of this auto-inhibitory mechanism.
• This provides a foundation for understanding K+ channel regulation and dysfunction.