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Structural Basis of Human KCNQ1 Modulation and Gating
1Laboratory of Molecular Neurobiology and Biophysics and Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Cell
|December 30, 2019
Summary
The KCNQ1 potassium channel, crucial for bodily functions, is regulated by KCNE3 and PIP2. Cryo-EM reveals KCNE3 stabilizes the channel, while PIP2 binding opens the pore.
Area of Science:
- Molecular and Cellular Biology
- Biophysics
- Ion Channel Physiology
Background:
- KCNQ1 (Kv7.1) is a voltage-dependent potassium channel critical for gastric acid secretion, salt/glucose homeostasis, and cardiac rhythm.
- Tissue-specific function is modulated by co-assembly with KCNE subunits (KCNE1-5).
- In non-excitable cells, KCNQ1 complexes with KCNE3, preventing closure at negative membrane potentials.
Purpose of the Study:
- To elucidate the structural mechanisms by which KCNE3 and PIP2 regulate KCNQ1 channel activity.
- To understand the role of PIP2 in KCNQ1 pore gating.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was employed to determine the structure of the KCNQ1-KCNE3 complex.
- Biochemical assays were used to assess the effect of PIP2 on channel function.
Main Results:
- Cryo-EM revealed that KCNE3's transmembrane helix interacts with KCNQ1, potentially locking its voltage sensor in a depolarized state.
- The KCNQ1 channel pore remains closed in the absence of PIP2.
- PIP2 binds to KCNQ1 within the inner membrane leaflet, inducing a significant conformational change that results in pore gate dilation.
Conclusions:
- KCNE3 acts as a regulator by stabilizing the KCNQ1 voltage sensor.
- PIP2 is essential for KCNQ1 channel opening, acting via a conserved mechanism involving pore gate dilation.
- This study provides atomic-level insights into KCNQ1 channel regulation by accessory subunits and lipids.
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