TY  - JOUR
AU  - Kondapuram, Mahesh
AU  - Frieg, Benedikt
AU  - Yüksel, Sezin
AU  - Schwabe, Tina
AU  - Sattler, Christian
AU  - Lelle, Marco
AU  - Schweinitz, Andrea
AU  - Schmauder, Ralf
AU  - Benndorf, Klaus
AU  - Gohlke, Holger
AU  - Kusch, Jana
TI  - Functional and structural characterization of interactions between opposite subunits in HCN pacemaker channels
JO  - Communications biology
VL  - 5
IS  - 1
SN  - 2399-3642
CY  - London
PB  - Springer Nature
M1  - FZJ-2022-02208
SP  - 430
PY  - 2022
AB  - 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 (MD) simulations to show that residue K464 of the C-linker is relevant for stabilizing the closed state of the mHCN2 channel by forming interactions with the opposite subunit. MD simulations revealed that in the K464E channel, a rotation of the intracellular domain relative to the channel pore is induced, which is similar to the cAMP-induced rotation, weakening the autoinhibitory effect of the unoccupied CL-CNBD region. We suggest that this CL-CNBD rotation is considerably involved in activation-induced affinity increase but only indirectly involved in gate modulation. The adopted poses shown herein are in excellent agreement with previous structural results.
LB  - PUB:(DE-HGF)16
C6  - 35534535
UR  - <Go to ISI:>//WOS:000792648600004
DO  - DOI:10.1038/s42003-022-03360-6
UR  - https://juser.fz-juelich.de/record/907779
ER  -