Key result
A triad interaction between KCNE3 and the S1 and S4 segments of KCNQ1 is required to retain the voltage sensor domain in the intermediate position, keeping the channel constitutively active.
Why the study?
How auxiliary KCNE proteins regulate the voltage sensor domain of the KCNQ1 voltage-gated K+ channel was largely unknown.
Tight binding between the S1 segment of KCNQ1 and KCNE3 is crucial for maintaining the constitutively open state of the KCNQ1-KCNE3 channel complex by preventing the S4 voltage sensor from moving to the down position.
Tetrameric voltage-gated K + channels have four identical voltage sensor domains, and they regulate channel gating. KCNQ1 (Kv7.1) is a voltage-gated K + channel, and its auxiliary subunit KCNE proteins dramatically regulate its gating. For example, KCNE3 makes KCNQ1 a constitutively open channel at physiological voltages by affecting the voltage sensor movement. However, how KCNE proteins regulate the voltage sensor domain is largely unknown. In this study, by utilizing the KCNQ1-KCNE3-calmodulin complex structure, we thoroughly surveyed amino acid residues on KCNE3 and the S1 segment of the KCNQ1 voltage sensor facing each other. By changing the side-chain bulkiness of these interacting amino acid residues, we found that the distance between the S1 segment and KCNE3 is elaborately optimized to achieve the constitutive activity. In addition, we identified two pairs of KCNQ1 and KCNE3 mutants that partially restored constitutive activity by co-expression. Our work suggests that tight binding of the S1 segment and KCNE3 is crucial for controlling the voltage sensor domains.
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Kasuya et al. (2021) studied this question. Site-directed mutagenesis of KCNQ1 and KCNE3 vs. Wild-type KCNQ1 and KCNE3 was evaluated on Voltage sensor domain movement (ΔF-160mV/ΔF60mV). A triad interaction between KCNE3 and the S1 and S4 segments of KCNQ1 is required to retain the voltage sensor domain in the intermediate position, keeping the channel constitutively active.
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