Journal Article

FZJ-2022-02208

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Functional and structural characterization of interactions between opposite subunits in HCN pacemaker channels

Kondapuram, M. ; Frieg, B.FZJ* ; Yüksel, S. ; Schwabe, T. ; Sattler, C. ; Lelle, M. ; Schweinitz, A. ; Schmauder, R. ; Benndorf, K. ; Gohlke, H. (Corresponding author)FZJ* ; Kusch, J. (Corresponding author)

2022
Springer Nature London

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Please use a persistent id in citations: http://hdl.handle.net/2128/31223  doi:10.1038/s42003-022-03360-6

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 (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.

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Contributing Institute(s):

1. Bioinformatik (IBG-4)
2. Jülich Supercomputing Center (JSC)
3. John von Neumann - Institut für Computing (NIC)
4. Strukturbiochemie (IBI-7)

Research Program(s):

1. 5111 - Domain-Specific Simulation & Data Life Cycle Labs (SDLs) and Research Groups (POF4-511) (POF4-511)
2. 2171 - Biological and environmental resources for sustainable use (POF4-217) (POF4-217)
3. Forschergruppe Gohlke (hkf7_20200501) (hkf7_20200501)
4. 5241 - Molecular Information Processing in Cellular Systems (POF4-524) (POF4-524)

Appears in the scientific report 2022

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