Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 14, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2017280118
Keywords
ion channels; thermosensing NMR; MD; voltage sensor domain
Categories
Funding
- NIH [P41GM103399, S10RR02781, S10RR08438, S10RR023438, S10RR025062, S10RR029220, R01NS081293, R35NS116850]
- University of Wisconsin-Madison
- NSF [DMB8415048, OIA-9977486, BIR-9214394, OCI-1053575, CHE-1829555]
- US Department of Agriculture
Ask authors/readers for more resources
By combining experimental results with molecular dynamics simulations, this study reveals that the engineered temperature-sensitive variant of the Shaker potassium channel has the same overall secondary structure as the wild-type channel, but exhibits local changes in backbone torsion angles near the substitution sites (V369S and F370S). Notably, these structural differences lead to increased hydration of specific regions in the temperature-sensitive variant at higher temperatures, highlighting the impact of subtle differences in primary structure on solvation and temperature-dependent activity.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available