TY  - JOUR
AU  - Pfleger, Christopher
AU  - Kusch, Jana
AU  - Kondapuram, Mahesh
AU  - Schwabe, Tina
AU  - Sattler, Christian
AU  - Benndorf, Klaus
AU  - Gohlke, Holger
TI  - Allosteric signaling in C-linker and cyclic nucleotide-binding domain of HCN2 channels
JO  - Biophysical journal
VL  - 120
IS  - 5
SN  - 0006-3495
CY  - Bethesda, Md.
PB  - Soc.
M1  - FZJ-2021-00939
SP  - 950-963
PY  - 2021
AB  - Opening of hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels is controlled by membrane hyperpolarization and binding of cyclic nucleotides to the tetrameric cyclic nucleotide-binding domain (CNBD), attached to the C-linker disk (CL). Confocal patch-clamp fluorometry revealed pronounced cooperativity of ligand binding among protomers. However, by which pathways allosteric signal transmission occurs remained elusive. Here, we investigate how changes in the structural dynamics of the CL-CNBD of mouse HCN2 upon cAMP binding relate to inter- and intrasubunit signal transmission. Applying a rigidity theory-based approach, we identify two intersubunit and one intrasubunit pathways that differ in allosteric coupling strength between cAMP binding sites or towards the CL. These predictions agree with results from electrophysiological and patch-clamp fluorometry experiments. Our results map out distinct routes within the CL-CNBD that modulate different cAMP binding responses in HCN2 channels. They signify that functionally relevant submodules may exist within and across structurally discernable subunits in HCN channels.
LB  - PUB:(DE-HGF)16
C6  - 33515603
UR  - <Go to ISI:>//WOS:000630953600021
DO  - DOI:10.1016/j.bpj.2021.01.017
UR  - https://juser.fz-juelich.de/record/890419
ER  -