title: A reduced mechanical model for cAMP-modulated gating in HCN channels.
abstract: We developed an in silico mechanical model to analyze the process of cAMP-induced conformational modulations in hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which conduct cations across the membrane of mammalian heart and brain cells. The structural analysis reveals a quaternary twist in the cytosolic parts of the four subunits in the channel tetramer. This motion augments the intrinsic dynamics of the very same protein structure. The pronounced differences between the cAMP bound and unbound form include a mutual interaction between the C-linker of the cyclic nucleotide binding domain (CNBD) and the linker between the S4 and S5 transmembrane domain of the channel. This allows a mechanistic annotation of the twisting motion in relation to the allosteric modulation of voltage-dependent gating of this channel by cAMP.
authors.affiliation: Department of Biology, TU Darmstadt, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Weißgraeber
authors.affiliation: Dept. of Biosciences, University of Milan, 20133 Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Saponaro
authors.affiliation: Department of Biology, TU Darmstadt, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Thiel
authors.affiliation: Department of Biology, TU Darmstadt, Germany.
authors.forename: Kay
authors.initials: K
authors.lastname: Hamacher
mesh_terms: D000818:Animals; D003198:Computer Simulation; D000242:Cyclic AMP / Q000378:metabolism*; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000737:chemistry / Q000378:metabolism*; D008322:Mammals; D011487:Protein Conformation; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism
chemical_list: D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D021122:Protein Subunits; D000242:Cyclic AMP