3OTF

Structural basis for the cAMP-dependent gating in human HCN4 channel

3OTF の概要

• エントリーDOI: 10.2210/pdb3otf/pdb
• 分子名称: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4, ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE (3 entities in total)
• 機能のキーワード: cyclic-nucleotide binding, transport protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 26217.65

構造登録者

Xu, X.,Vysotskaya, Z.V.,Liu, Q.,Zhou, L. (登録日: 2010-09-11, 公開日: 2010-10-13, 最終更新日: 2023-09-06)

主引用文献

Xu, X.,Vysotskaya, Z.V.,Liu, Q.,Zhou, L.
Structural basis for the cAMP-dependent gating in the human HCN4 channel.
J.Biol.Chem., 285:37082-37091, 2010

PubMed Abstract: Hyperpolarization-activated cAMP-regulated (HCN) channels play important physiological roles in both cardiovascular and central nervous systems. Among the four HCN isoforms, HCN2 and HCN4 show high expression levels in the human heart, with HCN4 being the major cardiac isoform. The previously published crystal structure of the mouse HCN2 (mHCN2) C-terminal fragment, including the C-linker and the cyclic-nucleotide binding domain (CNBD), has provided many insights into cAMP-dependent gating in HCN channels. However, structures of other mammalian HCN channel isoforms have been lacking. Here we used a combination of approaches including structural biology, biochemistry, and electrophysiology to study cAMP-dependent gating in HCN4 channel. First we solved the crystal structure of the C-terminal fragment of human HCN4 (hHCN4) channel at 2.4 Å. Overall we observed a high similarity between mHCN2 and hHCN4 crystal structures. Functional comparison between two isoforms revealed that compared with mHCN2, the hHCN4 protein exhibited marked different contributions to channel function, such as a ∼3-fold reduction in the response to cAMP. Guided by structural differences in the loop region between β4 and β5 strands, we identified residues that could partially account for the differences in response to cAMP between mHCN2 and hHCN4 proteins. Moreover, upon cAMP binding, the hHCN4 C-terminal protein exerts a much prolonged effect in channel deactivation that could have significant physiological contributions.

PubMed: 20829353
DOI: 10.1074/jbc.M110.152033

実験手法

X-RAY DIFFRACTION (2.4 Å)