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  - bioRxiv beta
CY  - Cold Spring Harbor
PB  - Cold Spring Harbor Laboratory, NY
M1  - FZJ-2021-01114
PY  - 2020
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 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.
LB  - PUB:(DE-HGF)16
DO  - DOI:10.1101/2020.09.21.305797
UR  - https://juser.fz-juelich.de/record/890666
ER  -