2MLE

NMR structure of the C-domain of troponin C bound to the anchoring region of troponin I

Summary for 2MLE

• Entry DOI: 10.2210/pdb2mle/pdb
• Related: 2MLF
• NMR Information: BMRB: 19816
• Descriptor: Troponin C, slow skeletal and cardiac muscles, CALCIUM ION (2 entities in total)
• Functional Keywords: troponin c, metal binding protein, troponin i, ef-hand, cardiac troponin
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 8449.36

Authors

Robertson, I.M.,Baryshnikova, O.K.,Mercier, P.,Sykes, B.D. (deposition date: 2014-02-26, release date: 2014-03-12, Last modification date: 2024-05-15)

Primary citation

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

Experimental method

SOLUTION NMR