3U0Z
Tetramerization dynamics of the C-terminus underlies isoform-specific cAMP-gating in HCN channels
Summary for 3U0Z
| Entry DOI | 10.2210/pdb3u0z/pdb |
| Related | 1Q43 3OTF 3U10 3U11 |
| Descriptor | Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1, ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE (3 entities in total) |
| Functional Keywords | helix, beta sheet, transport protein, cnmp binding |
| Biological source | Mus musculus (mouse) |
| Cellular location | Membrane; Multi-pass membrane protein: O88704 |
| Total number of polymer chains | 2 |
| Total formula weight | 49720.65 |
| Authors | Lolicato, M.,Nardini, M.,Gazzarrini, S.,Moller, S.,Bertinetti, D.,Herberg, F.W.,Bolognesi, M.,Martin, H.,Fasolini, M.,Bertrand, J.A.,Arrigoni, C.,Thiel, G.,Moroni, A. (deposition date: 2011-09-29, release date: 2011-10-26, Last modification date: 2023-11-01) |
| Primary citation | Lolicato, M.,Nardini, M.,Gazzarrini, S.,Moller, S.,Bertinetti, D.,Herberg, F.W.,Bolognesi, M.,Martin, H.,Fasolini, M.,Bertrand, J.A.,Arrigoni, C.,Thiel, G.,Moroni, A. Tetramerization dynamics of C-terminal domain underlies isoform-specific cAMP gating in hyperpolarization-activated cyclic nucleotide-gated channels. J.Biol.Chem., 286:44811-44820, 2011 Cited by PubMed Abstract: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are dually activated by hyperpolarization and binding of cAMP to their cyclic nucleotide binding domain (CNBD). HCN isoforms respond differently to cAMP; binding of cAMP shifts activation of HCN2 and HCN4 by 17 mV but shifts that of HCN1 by only 2-4 mV. To explain the peculiarity of HCN1, we solved the crystal structures and performed a biochemical-biophysical characterization of the C-terminal domain (C-linker plus CNBD) of the three isoforms. Our main finding is that tetramerization of the C-terminal domain of HCN1 occurs at basal cAMP concentrations, whereas those of HCN2 and HCN4 require cAMP saturating levels. Therefore, HCN1 responds less markedly than HCN2 and HCN4 to cAMP increase because its CNBD is already partly tetrameric. This is confirmed by voltage clamp experiments showing that the right-shifted position of V(½) in HCN1 is correlated with its propensity to tetramerize in vitro. These data underscore that ligand-induced CNBD tetramerization removes tonic inhibition from the pore of HCN channels. PubMed: 22006928DOI: 10.1074/jbc.M111.297606 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.9 Å) |
Structure validation
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