Journal Article

FZJ-2021-00939

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Allosteric signaling in C-linker and cyclic nucleotide-binding domain of HCN2 channels

Pfleger, C. ; Kusch, J. ; Kondapuram, M. ; Schwabe, T. ; Sattler, C. ; Benndorf, K. ; Gohlke, H. (Corresponding author)FZJ*

2021
Soc. Bethesda, Md.

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Please use a persistent id in citations: http://hdl.handle.net/2128/27391  doi:10.1016/j.bpj.2021.01.017

Abstract: 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.

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Contributing Institute(s):

1. Jülich Supercomputing Center (JSC)
2. John von Neumann - Institut für Computing (NIC)
3. Strukturbiochemie (IBI-7)

Research Program(s):

1. 5111 - Domain-Specific Simulation & Data Life Cycle Labs (SDLs) and Research Groups (POF4-511) (POF4-511)
2. Forschergruppe Gohlke (hkf7_20200501) (hkf7_20200501)

Appears in the scientific report 2021

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Essential Science Indicators ; IF < 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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