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

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 54 transmembrane helices insert cooperatively, because the S3, 54, and 53-54 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, 53 can both insert into the membrane by itself and mediate the insertion of the S3-54 segment in the absence of 52. An engineered KAT1 53-54 segment in which the hydrophobicity of 53 was increased or where 53 was replaced by Shaker 53 behaves as Shaker S3-54. Electrostatic interactions among charged residues in 52, S3, and 54, 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. [ABSTRACT FROM AUTHOR]