Functional and structural characterization of interactions between opposite subunits in HCN pacemaker channels

dc.contributor.authorKondapuram, Mahesh
dc.contributor.authorFrieg, Benedikt
dc.contributor.authorYüksel, Sezin
dc.contributor.authorSchwabe, Tina
dc.contributor.authorSattler, Christian
dc.contributor.authorLelle, Marco
dc.contributor.authorSchweinitz, Andrea
dc.contributor.authorSchmauder, Ralf
dc.contributor.authorBenndorf, Klaus
dc.contributor.authorGohlke, Holger
dc.contributor.authorKusch, Jana
dc.date.accessioned2021-08-05T19:55:28Z
dc.date.available2021-08-05T19:55:28Z
dc.date.issued2021-08-05
dc.description.abstractHyperpolarization-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.en
dc.identifier.urihttps://researchdata.hhu.de/handle/entry/98
dc.identifier.urihttp://dx.doi.org/10.25838/d5p-27
dc.language.isoenen
dc.publisherN/Aen
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/us/*
dc.subjectHCN channelen
dc.subjectmolecular dynamics simulationsen
dc.subjectsubunit interactionen
dc.subjectpatch-clamp techniqueen
dc.subjectconfocal patch-clamp fluorometryen
dc.titleFunctional and structural characterization of interactions between opposite subunits in HCN pacemaker channelsen
dc.typeDataseten

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