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Electromechanical coupling in the hyperpolarization-activated K+ channel KAT1
Michael David Clark1, Gustavo F Contreras1, Rong Shen1
1Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA.
Nature
|May 29, 2020
Summary
Researchers elucidated the gating polarity mechanism in voltage-gated potassium (Kv) channels using the KAT1 structure. Direct sensor-pore interactions, not allostery, primarily determine channel gating direction.
Area of Science:
- Molecular Biology
- Biophysics
- Structural Biology
Background:
- Voltage-gated potassium (Kv) channels are crucial for electrical signaling and cell volume regulation.
- While voltage sensors transduce electric fields, the determinants of Kv channel gating polarity are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanism of electromechanical coupling and gating polarity in non-domain-swapped Kv channels.
- To determine the structural basis for hyperpolarization activation in the KAT1 channel.
Main Methods:
- Cryo-electron microscopy to determine the structure of the KAT1 channel.
- Structure-guided mutagenesis and functional electrophysiology to evaluate mutant channel activity.
Main Results:
- The structure of KAT1 revealed a depolarized voltage sensor interacting with a closed pore domain via direct and indirect interfaces.
- Mutational analysis identified direct interactions between the voltage sensor and the C-linker hairpin as the primary determinant of gating polarity.
- A direct-coupling mechanism involving S4 helix motion and C-linker reorientation was proposed.
Conclusions:
- Direct sensor-pore interactions, specifically between the voltage sensor and adjacent pore subunit C-linker, dictate Kv channel gating polarity.
- This direct-coupling mechanism offers a new perspective contrasting with allosteric models and may link depolarization- and hyperpolarization-activated channels.
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