Helix breaking transition in the S4 of HCN channel is critical for hyperpolarization-dependent gating.
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Kasimova MA, Tewari D, Cowgill JB, Ursuleaz WC, Lin JL, Delemotte L, Chanda B
Elife 8 (-) - [2019-11-27; online 2019-11-27]
In contrast to most voltage-gated ion channels, hyperpolarization- and cAMP gated (HCN) ion channels open on hyperpolarization. Structure-function studies show that the voltage-sensor of HCN channels are unique but the mechanisms that determine gating polarity remain poorly understood. All-atom molecular dynamics simulations (~20 μs) of HCN1 channel under hyperpolarization reveals an initial downward movement of the S4 voltage-sensor but following the transfer of last gating charge, the S4 breaks into two sub-helices with the lower sub-helix becoming parallel to the membrane. Functional studies on bipolar channels show that the gating polarity strongly correlates with helical turn propensity of the substituents at the breakpoint. Remarkably, in a proto-HCN background, the replacement of breakpoint serine with a bulky hydrophobic amino acid is sufficient to completely flip the gating polarity from inward to outward-rectifying. Our studies reveal an unexpected mechanism of inward rectification involving a linker sub-helix emerging from HCN S4 during hyperpolarization.
PubMed 31774399
DOI 10.7554/eLife.53400
Crossref 10.7554/eLife.53400
pii: 53400
pmc: PMC6904216