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Structure of the Nav1.4-β1 Complex from Electric Eel
Zhen Yan1, Qiang Zhou1, Lin Wang1
1State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China; Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, China.
Cell
|July 25, 2017
Summary
We determined the cryo-EM structure of the electric eel sodium channel (Nav) with its β1 subunit. This reveals how the channel
Area of Science:
- Structural Biology
- Neuroscience
- Biophysics
Background:
- Voltage-gated sodium channels (Nav) are crucial for electrical signaling in excitable cells.
- Understanding Nav channel structure is key to deciphering action potential generation and propagation.
- Previous structural studies have provided insights into closed states, but open states remain less understood.
Purpose of the Study:
- To determine the cryo-electron microscopy (cryo-EM) structure of the electric eel Nav1.4 channel (EeNav1.4) in complex with the β1 subunit.
- To elucidate the structural basis of channel gating and fast inactivation.
- To provide insights into the mechanism of action potential propagation.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was used to determine the structure of EeNav1.4 complexed with the β1 subunit.
- High-resolution structural analysis at 4.0 Å resolution.
- Comparative structural analysis with previously determined closed Nav channel structures.
Main Results:
- The cryo-EM structure of EeNav1.4 with the β1 subunit was resolved at 4.0 Å resolution.
- The β1 subunit's immunoglobulin domain interacts with extracellular loops, and its transmembrane helix contacts voltage-sensing domain III (VSDIII).
- Voltage-sensing domains are in the 'up' conformation, indicating an open state, with an intracellular gate held open by a digitonin-like molecule.
- Structural comparisons reveal coupling between gating charge transfer and pore dilation, involving multiple channel segments.
- The IFM motif, responsible for fast inactivation, is positioned within repeats III and IV, suggesting an allosteric blocking mechanism.
Conclusions:
- The determined structure provides a high-resolution snapshot of an open state of a voltage-gated sodium channel.
- The interaction of the β1 subunit influences channel gating and stability.
- The findings elucidate the mechanism of fast inactivation and pore opening, offering targets for therapeutic interventions.
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