The calcium sensitizer drug MCI-154 binds the structural C-terminal domain of cardiac troponin C

被引:7
|
作者
Li, Monica X. [1 ]
Gelozia, Shorena [2 ]
Danmaliki, Gaddafi, I [3 ]
Wen, Yurong [3 ,4 ]
Liu, Philip B. [1 ]
Lemieux, M. Joanne [3 ]
West, Frederick G. [2 ]
Sykes, Brian D. [3 ]
Hwang, Peter M. [1 ,3 ]
机构
[1] Univ Alberta, Dept Med, Edmonton, AB T6G 2R3, Canada
[2] Univ Alberta, Dept Chem, Edmonton, AB T6G 2G2, Canada
[3] Univ Alberta, Dept Biochem, Edmonton, AB T6G 2H7, Canada
[4] Xi An Jiao Tong Univ, Sch Life Sci & Technol, Xian, Peoples R China
基金
加拿大健康研究院;
关键词
Solution NMR spectroscopy; Calcium sensitizer; Drug binding; Protein-protein interaction;
D O I
10.1016/j.bbrep.2018.10.012
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The compound MCI-154 was previously shown to increase the calcium sensitivity of cardiac muscle contraction. Using solution NMR spectroscopy, we demonstrate that MCI-154 interacts with the calcium-sensing subunit of the cardiac troponin complex, cardiac troponin C (cTnC). Surprisingly, however, it binds only to the structural C-terminal domain of cTnC (cCTnC), and not to the regulatory N-terminal domain (cNTnC) that determines the calcium sensitivity of cardiac muscle. Physiologically, cTnC is always bound to cardiac troponin I (cTnI), so we examined its interaction with MCI-154 in the presence of two soluble constructs, cTnI(1-77) and cTnI(135-209), which contain all of the segments of cTnI known to interact with cTnC. Neither the cTnC-cTnI(1-77) complex nor the cTnC-cTnI(135-209) complex binds to MCI-154. Since residues 39-60 of cTnI are known to bind tightly to the cCTnC domain to form a structured core that is invariant throughout the cardiac cycle, we conclude that MCI-154 does not bind to cTnC when it is part of the intact cardiac troponin complex. Thus, MCI-154 likely exerts its calcium sensitizing effect by interacting with a target other than cardiac troponin.
引用
收藏
页码:145 / 151
页数:7
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