Solution structure of the sodium channel inactivation gate

Area of Science:

• Molecular biology
• Biophysics
• Neuroscience

Background:

• Fast inactivation of sodium channels is crucial for action potential propagation.
• A cytoplasmic loop, acting as a hinged lid, is proposed to mediate this inactivation.
• The IFM motif within this loop is thought to function as a hydrophobic latch.

Purpose of the Study:

• To determine the structure of the isolated sodium channel inactivation gate.
• To elucidate the mechanism by which the inactivation gate occludes the ion pore.
• To investigate the role of the IFM triad and adjacent residues in fast inactivation.

Main Methods:

• Nuclear Magnetic Resonance (NMR) spectroscopy was used to determine the solution structure of the isolated inactivation gate.
• Substituted cysteine accessibility mutagenesis experiments were performed to probe the role of specific residues.

Main Results:

• The NMR structure revealed a stably folded core containing the IFM latch motif, supported by an alpha-helix and N-terminal turn.
• This folded core appears to pivot on a flexible hinge region to occlude the pore.
• Mutagenesis data confirmed the essential role of the IFM triad and adjacent Threonine (Thr) in the latch mechanism.

Conclusions:

• The study supports a model where the folded inactivation gate core, containing the IFM latch, pivots to occlude the sodium channel pore.
• The IFM triad and Thr residues are critical for the fast inactivation process.
• Distinct roles for residues within the IFMT motif in fast inactivation are suggested.