期刊
BIOCHEMISTRY
卷 47, 期 41, 页码 10950-10960出版社
AMER CHEMICAL SOC
DOI: 10.1021/bi801165c
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资金
- Alberta Heritage Foundation for Medical Research scholarship
- Canadian Institutes for Health Research
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 mu M) compared to that of the wild type (K(D) < 1 mu M). Overall, the structure and dynamics of the G159D center dot CTnI(34-71) complex were very similar to those of the cCTnC center dot 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 center dot cTnI(34-71) and cCTnC center dot 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.
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