Daniel T. Infield, Kimberly Matulef, Jason D. Galpin, Kin Lam, Emad
Tajkhorshid, Christopher A. Ahern, and Francis I. Valiyaveetil.
Main-chain mutagenesis reveals intrahelical coupling in an ion
channel voltage-sensor.
Nature Communications, 9:5055, 2018.
(PMC: PMC6265297)
INFI2018-ET
Membrane proteins are universal signal decoders. The helical
transmembrane segments of these proteins play central roles in sensory
transduction, yet the mechanistic contributions of secondary structure
remain unresolved. To investigate the role of main-chain hydrogen bonding
on transmembrane function, we encoded amide-to-ester substitutions at
sites throughout the S4 voltage-sensing segment of Shaker potassium
channels, a region that undergoes rapid, voltage-driven movement during
channel gating. Functional measurements of ester-harboring channels
highlight a transitional region between -helical and
segments where hydrogen bond removal is particularly disruptive to voltage-
gating. Simulations of an active voltage-sensor reveal that this region
features a dynamic hydrogen bonding pattern and that its helical structure is
reliant upon amide support. Overall, the data highlight the specialized role of
main-chain chemistry in the mechanism of voltage-sensing; other catalytic
transmembrane segments may enlist similar strategies in signal transduction
mechanisms.
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