Contribution of hydrophobic and electrostatic interactions to the membrane integration of the Shaker K + channel voltage sensor domain

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Abstract
Membrane-embedded voltage-sensor domains in voltage-dependent potassium channels (Kv channels) contain an impressive number of charged residues. How can such highly charged protein domains be efficiently inserted into biological membranes? In the plant Kv channel KAT1, the S2, S3, and S4 transmembrane helices insert cooperatively, because the S3, S4, and S3–S4 segments do not have any membrane insertion ability by themselves. Here we show that, in the Drosophila Shaker Kv channel, which has a more hydrophobic S3 helix than KAT1, S3 can both insert into the membrane by itself and mediate the insertion of the S3–S4 segment in the absence of S2. An engineered KAT1 S3–S4 segment in which the hydrophobicity of S3 was increased or where S3 was replaced by Shaker S3 behaves as Shaker S3–S4. Electrostatic interactions among charged residues in S2, S3, and S4, including the salt bridges between E283 or E293 in S2 and R368 in S4, are required for fully efficient membrane insertion of the Shaker voltage-sensor domain. These results suggest that cooperative insertion of the voltage-sensor transmembrane helices is a property common to Kv channels and that the degree of cooperativity depends on a balance between electrostatic and hydrophobic forces.