title: Cyclic Purine and Pyrimidine Nucleotides Bind to the HCN2 Ion Channel and Variably Promote C-Terminal Domain Interactions and Opening.
abstract: Cyclic AMP is thought to facilitate the opening of the HCN2 channel by binding to a C-terminal domain and promoting or inhibiting interactions between subunits. Here, we correlated the ability of cyclic nucleotides to promote interactions of isolated HCN2 C-terminal domains in solution with their ability to facilitate channel opening. Cyclic IMP, a cyclic purine nucleotide, and cCMP, a cyclic pyrimidine nucleotide, bind to a C-terminal domain containing the cyclic nucleotide-binding domain but, in contrast to other cyclic nucleotides examined, fail to promote its oligomerization, and produce only modest facilitation of opening of the full-length channel. Comparisons between ligand bound structures identify a region between the sixth and seventh β strands and the distal C helix as important for facilitation and tight binding. We propose that promotion of interactions between the C-terminal domains by a given ligand contribute to its ability to facilitate opening of the full-length channel.
authors: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors: Leo C T
authors: LCT
authors: Ng
authors: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors: Igor
authors: I
authors: Putrenko
authors: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors: Victoria
authors: V
authors: Baronas
authors: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors: Filip
authors: F
authors: Van Petegem
authors: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address: eaaccili@mail.ubc.ca.
authors: Eric A
authors: EA
authors: Accili
mesh_terms: D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003563:Cyclic CMP / Q000378:metabolism*; D007289:Cyclic IMP / Q000378:metabolism*; D000067493:Dynamic Light Scattering; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D015221:Potassium Channels / Q000737:chemistry* / Q000378:metabolism*; D000072417:Protein Domains; D017433:Protein Structure, Secondary
chemical_list: C578711:Hcn2 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels; D007289:Cyclic IMP; D003563:Cyclic CMP