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000890419 1001_ $$0P:(DE-HGF)0$$aPfleger, Christopher$$b0
000890419 245__ $$aAllosteric signaling in C-linker and cyclic nucleotide-binding domain of HCN2 channels
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000890419 520__ $$aOpening of hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels is controlled by membrane hyperpolarization and binding of cyclic nucleotides to the tetrameric cyclic nucleotide-binding domain (CNBD), attached to the C-linker disk (CL). Confocal patch-clamp fluorometry revealed pronounced cooperativity of ligand binding among protomers. However, by which pathways allosteric signal transmission occurs remained elusive. Here, we investigate how changes in the structural dynamics of the CL-CNBD of mouse HCN2 upon cAMP binding relate to inter- and intrasubunit signal transmission. Applying a rigidity theory-based approach, we identify two intersubunit and one intrasubunit pathways that differ in allosteric coupling strength between cAMP binding sites or towards the CL. These predictions agree with results from electrophysiological and patch-clamp fluorometry experiments. Our results map out distinct routes within the CL-CNBD that modulate different cAMP binding responses in HCN2 channels. They signify that functionally relevant submodules may exist within and across structurally discernable subunits in HCN channels.
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000890419 7001_ $$0P:(DE-HGF)0$$aKusch, Jana$$b1
000890419 7001_ $$0P:(DE-HGF)0$$aKondapuram, Mahesh$$b2
000890419 7001_ $$0P:(DE-HGF)0$$aSchwabe, Tina$$b3
000890419 7001_ $$0P:(DE-HGF)0$$aSattler, Christian$$b4
000890419 7001_ $$0P:(DE-HGF)0$$aBenndorf, Klaus$$b5
000890419 7001_ $$0P:(DE-Juel1)172663$$aGohlke, Holger$$b6$$eCorresponding author$$ufzj
000890419 773__ $$0PERI:(DE-600)1477214-0$$a10.1016/j.bpj.2021.01.017$$gp. S0006349521000576$$n5$$p950-963$$tBiophysical journal$$v120$$x0006-3495$$y2021
000890419 8564_ $$uhttps://juser.fz-juelich.de/record/890419/files/HCN2_Allostery_SI_BiophysJ_rev_final.pdf$$yRestricted
000890419 8564_ $$uhttps://juser.fz-juelich.de/record/890419/files/HCN2_Allostery_main_BiophysJ_rev_final.pdf$$yPublished on 2021-01-28. Available in OpenAccess from 2022-01-28.
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