6DAF

2.4 Angstrom crystal structure of the F141L Ca/CaM:CaV1.2 IQ domain complex

6DAF の概要

• エントリーDOI: 10.2210/pdb6daf/pdb
• 分子名称: Calmodulin-1, Voltage-dependent L-type calcium channel subunit alpha-1C, CALCIUM ION, ... (4 entities in total)
• 機能のキーワード: calmodulin, mutant, complex, calcium binding protein-membrane protein complex, calcium binding protein/membrane protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 42333.23

構造登録者

Wang, K.,Van Petegem, F. (登録日: 2018-05-01, 公開日: 2018-10-17, 最終更新日: 2023-10-04)

主引用文献

Wang, K.,Holt, C.,Lu, J.,Brohus, M.,Larsen, K.T.,Overgaard, M.T.,Wimmer, R.,Van Petegem, F.
Arrhythmia mutations in calmodulin cause conformational changes that affect interactions with the cardiac voltage-gated calcium channel.
Proc. Natl. Acad. Sci. U.S.A., 115:E10556-E10565, 2018

PubMed Abstract: Calmodulin (CaM) represents one of the most conserved proteins among eukaryotes and is known to bind and modulate more than a 100 targets. Recently, several disease-associated mutations have been identified in the genes that are causative of severe cardiac arrhythmia syndromes. Although several mutations have been shown to affect the function of various cardiac ion channels, direct structural insights into any CaM disease mutation have been lacking. Here we report a crystallographic and NMR investigation of several disease mutant CaMs, linked to long-QT syndrome, in complex with the IQ domain of the cardiac voltage-gated calcium channel (Ca1.2). Surprisingly, two mutants (D95V, N97I) cause a major distortion of the C-terminal lobe, resulting in a pathological conformation not reported before. These structural changes result in altered interactions with the Ca1.2 IQ domain. Another mutation (N97S) reduces the affinity for Ca by introducing strain in EF hand 3. A fourth mutant (F141L) shows structural changes in the Ca-free state that increase the affinity for the IQ domain. These results thus show that different mechanisms underlie the ability of CaM disease mutations to affect Ca-dependent inactivation of the voltage-gated calcium channel.

PubMed: 30348784
DOI: 10.1073/pnas.1808733115

実験手法

X-RAY DIFFRACTION (2.4 Å)