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A schematic representation of cardiac troponin in relation to the thin filament in the absence and presence of Ca 2+ . The inhibitory region of TnI (IR), and the N-terminal and Cterminal domains of TnT are not clearly observed in the crystal structure, likely due to their inherent flexibility (see text). The red dots represent Ca 2+ ions. The figure is adapted from Takeda, 2003 (Li, 2009).
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... They found that another cTnC mutation, L48Q, enhanced Ca 2+ affinity and reduced the SL-dependence of myofilament Ca 2+ sensitivity. This finding has several important implications: 1) the L29Q cTnC mutation should impact LDA that is an important component of the Starling relationship of the heart; 2) the high myofilament Ca 2+ sensitivity of the L29Q cTnC mutation at the shortest SL (1.9 mm) which corresponds to near peak systolic conditions could alter Ca 2+ dynamics within the cardiomyocyte with the potential of being arrhythmogenic [49][50][51]; and 3) the strong impact of the L29Q cTnC on the LDA could also be an explanation for the discrepant results found in this study between the data from TFP and that from SCM. Furthermore, it may also provide an explanation for the difference in results between our previous ( [12] and present study) which showed an increase in Ca 2+ sensitivity with the L29Q cTnC mutation and others which did not [8,11,14]. ...
... The L29Q cTnC mutation renders the cNTnC in a more ''open'' conformation compared to the constructs containing WT cTnC especially when cTnI is pseudo-phosphorylated (Figs. 4 B and C). Though Leu29 does not make key contacts with residues to form the hydrophobic core of cNTnC, such as in the L48Q cTnC mutant (49), the L29Q cTnC mutation does have a small global effect on the conformation of cNTnC. The L29Q cTnC mutations promotes a more open conformation that could have increased the affinity of the cTnI switch peptide for cNTnC, reduced its inhibitory function on actin and impeded the muscle relaxation process. ...
The Ca(2+) binding properties of the FHC-associated cardiac troponin C (cTnC) mutation L29Q were examined in isolated cTnC, troponin complexes, reconstituted thin filament preparations, and skinned cardiomyocytes. While higher Ca(2+) binding affinity was apparent for the L29Q mutant in isolated cTnC, this phenomenon was not observed in the cTn complex. At the level of the thin filament in the presence of phosphomimetic TnI, L29Q cTnC further reduced the Ca(2+) affinity by 27% in the steady-state measurement and increased the Ca(2+) dissociation rate by 20% in the kinetic studies. Molecular dynamics simulations suggest that L29Q destabilizes the conformation of cNTnC in the presence of phosphomimetic cTnI and potentially modulates the Ca(2+) sensitivity due to the changes of the opening/closing equilibrium of cNTnC. In the skinned cardiomyocyte preparation, L29Q cTnC increased Ca(2+) sensitivity in a highly sarcomere length (SL)-dependent manner. The well-established reduction of Ca(2+) sensitivity by phosphomimetic cTnI was diminished by 68% in the presence of the mutation and it also depressed the SL-dependent increase in myofilament Ca(2+) sensitivity. This might result from its modified interaction with cTnI which altered the feedback effects of cross-bridges on the L29Q cTnC-cTnI-Tm complex. This study demonstrates that the L29Q mutation alters the contractility and the functional effects of the phosphomimetic cTnI in both thin filament and single skinned cardiomyocytes and importantly that this effect is highly sarcomere length dependent.
