2MLF

NMR structure of the dilated cardiomyopathy mutation G159D in troponin C bound to the anchoring region of troponin I

2MLF の概要

• エントリーDOI: 10.2210/pdb2mlf/pdb
• 関連するPDBエントリー: 2MLE
• NMR情報: BMRB: 19817
• 分子名称: Troponin C, slow skeletal and cardiac muscles, CALCIUM ION (2 entities in total)
• 機能のキーワード: troponin c, metal binding protein, dilated cardiomyopathy, g159d, ef-hand
• 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: 8507.40

構造登録者

Baryshnikova, O.K.,Robertson, I.M.,Mercier, P.,Sykes, B.D. (登録日: 2014-02-26, 公開日: 2014-03-12, 最終更新日: 2024-05-15)

主引用文献

Baryshnikova, O.K.,Robertson, I.M.,Mercier, P.,Sykes, B.D.
The dilated cardiomyopathy G159D mutation in cardiac troponin C weakens the anchoring interaction with troponin I.
Biochemistry, 47:10950-10960, 2008

PubMed Abstract: NMR spectroscopy has been employed to elucidate the molecular consequences of the DCM G159D mutation on the structure and dynamics of troponin C, and its interaction with troponin I (TnI). Since the molecular effects of human mutations are often subtle, all NMR experiments were conducted as direct side-by-side comparisons of the wild-type C-domain of troponin C (cCTnC) and the mutant protein, G159D. With the mutation, the affinity toward the anchoring region of cTnI (cTnI 34-71) was reduced ( K D = 3.0 +/- 0.6 microM) compared to that of the wild type ( K D < 1 microM). Overall, the structure and dynamics of the G159D.cTnI 34-71 complex were very similar to those of the cCTnC.cTnI 34-71 complex. There were, however, significant changes in the (1)H, (13)C, and (15)N NMR chemical shifts, especially for the residues in direct contact with cTnI 34-71, and the changes in NOE connectivity patterns between the G159D.cTnI 34-71 and cCTnC.cTnI 34-71 complexes. Thus, the most parsimonious hypothesis is that the development of disease results from the poor anchoring of cTnI to cCTnC, with the resulting increase in the level of acto-myosin inhibition in agreement with physiological data. Another possibility is that long-range electrostatic interactions affect the binding of the inhibitory and switch regions of cTnI (cTnI 128-147 and cTnI 147-163) and/or the cardiac specific N-terminus of cTnI (cTnI 1-29) to the N-domain of cTnC. These important interactions are all spatially close in the X-ray structure of the cardiac TnC core.

PubMed: 18803402
DOI: 10.1021/bi801165c

実験手法

SOLUTION NMR