Key result
The engineered temperature-sensitive variant of the Shaker potassium channel voltage sensor domain exhibits increased hydration of the voltage-sensing arginines and the S4-S5 linker helix at higher temperatures compared to the wild-type channel.
Why the study?
Understanding of the structural mechanisms underlying ion channel temperature sensing remains limited, partly due to challenges combining high-resolution structural analysis with temperature stimuli.
Subtle primary structure differences in engineered temperature-sensitive K+ channels cause large-scale changes in solvation, explaining increased temperature-dependent activity.
No immediate clinical implications; leaves open whether solvation changes drive temperature sensitivity in native cardiac channels.
Temperature-dependent regulation of ion channel activity is critical for a variety of physiological processes ranging from immune response to perception of noxious stimuli. Our understanding of the structural mechanisms that underlie temperature sensing remains limited, in part due to the difficulty of combining high-resolution structural analysis with temperature stimulus. Here, we use NMR to compare the temperature-dependent behavior of Shaker potassium channel voltage sensor domain (WT-VSD) to its engineered temperature sensitive (TS-VSD) variant. Further insight into the molecular basis for temperature-dependent behavior is obtained by analyzing the experimental results together with molecular dynamics simulations. Our studies reveal that the overall secondary structure of the engineered TS-VSD is identical to the wild-type channels except for local changes in backbone torsion angles near the site of substitution (V369S and F370S). Remarkably however, these structural differences result in increased hydration of the voltage-sensing arginines and the S4-S5 linker helix in the TS-VSD at higher temperatures, in contrast to the WT-VSD. These findings highlight how subtle differences in the primary structure can result in large-scale changes in solvation and thereby confer increased temperature-dependent activity beyond that predicted by linear summation of solvation energies of individual substituents.
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Chen et al. (2021) studied this question. Engineered temperature-sensitive S2bot mutation (TS-VSD) vs. Wild-type Shaker potassium channel voltage sensor domain (WT-VSD) was evaluated on Temperature-dependent conformational change and water accessibility (hydration). The engineered temperature-sensitive variant of the Shaker potassium channel voltage sensor domain exhibits increased hydration of the voltage-sensing arginines and the S4-S5 linker helix at higher temperatures compared to the wild-type channel.
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