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@ARTICLE{Kondapuram:890666,
author = {Kondapuram, Mahesh and Frieg, Benedikt and Yüksel, Sezin
and Schwabe, Tina and Sattler, Christian and Lelle, Marco
and Schweinitz, Andrea and Schmauder, Ralf and Benndorf,
Klaus and Gohlke, Holger and Kusch, Jana},
title = {{F}unctional and structural characterization of
interactions between opposite subunits in {HCN} pacemaker
channels},
journal = {bioRxiv beta},
address = {Cold Spring Harbor},
publisher = {Cold Spring Harbor Laboratory, NY},
reportid = {FZJ-2021-01114},
year = {2020},
abstract = {Hyperpolarization-activated and cyclic nucleotide (HCN)
modulated channels are tetrameric cation channels. In each
of the four subunits, the intracellular cyclic
nucleotide-binding domain (CNBD) is coupled to the
transmembrane domain via a helical structure, the C-linker.
High-resolution channel structures suggest that the C-linker
enables functionally relevant interactions with the opposite
subunit, which might be critical for coupling the
conformational changes in the CNBD to the channel pore. We
combined mutagenesis, patch-clamp technique, confocal
patch-clamp fluorometry, and molecular dynamics simulations
to show that residue K464 of the C-linker is essential for
stabilizing the closed state of the mHCN2 channel by forming
interactions with the opposite subunit. MD simulations
revealed that both cAMP and K464E induce a rotation of the
intracellular domain relative to the channel pore, weakening
the autoinhibitory effect of the unoccupied CL-CNBD region.
The adopted poses are in excellent agreement with structural
results.},
ddc = {570},
typ = {PUB:(DE-HGF)16},
doi = {10.1101/2020.09.21.305797},
url = {https://juser.fz-juelich.de/record/890666},
}