Pflugers Arch 1998 Dec 01;4371:114-22. doi: 10.1007/s004240050755.

Stabilization of a channel's open state by a hydrophobic residue in the sixth membrane-spanning segment (S6) of rKv1.4.

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We report the effects of mutating a threonine residue at position 529 (T529) in the middle of the S6 segment of rKv1.4 on the voltage-dependence and kinetics of activation and deactivation. Replacing T529 with glycine (no side chain) or with a residue that has a hydrophobic side chain (T529L, T529I, T529V, T529A, or T529F) caused a slowing of deactivation, along with a negative shift in the activation curve and a voltage-dependent slowing of activation. Numerical simulation showed that these effects could be reproduced by decreasing the rate constant for a transition from open to closed states. The degree of slowing of deactivation largely correlated with the degree of increase in 529 side-chain hydrophobicity. Specifically, the 529 mutation-induced alteration in free energy change accompanying deactivation per channel could be accounted for by the increase in free energy needed to transfer the 529 side chain of one subunit from a hydrophobic environment to an aqueous environment. We propose that in the open state, the 529 side chain faces a hydrophobic protein interior. The rate-limiting step in channel deactivation includes a conformational change in one subunit's S6 segment, moving its 529 side chain to face the aqueous lumen of the pore.

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