3U10

Tetramerization dynamics of the C-terminus underlies isoform-specific cAMP-gating in HCN channels

3U10 の概要

• エントリーDOI: 10.2210/pdb3u10/pdb
• 関連するPDBエントリー: 1Q43 3OTF 3U0Z 3U11
• 分子名称: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2, ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE (3 entities in total)
• 機能のキーワード: transport protein
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Multi-pass membrane protein: Q9UL51
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 24860.35

構造登録者

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. (登録日: 2011-09-29, 公開日: 2011-10-26, 最終更新日: 2023-11-01)

主引用文献

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

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: 22006928
DOI: 10.1074/jbc.M111.297606

実験手法

X-RAY DIFFRACTION (2.3 Å)