Familial Hypertrophic Cardiomyopathy Related Cardiac Troponin C L29Q Mutation Alters Length-Dependent Activation and Functional Effects of Phosphomimetic Troponin I*
Open Access
- 18 November 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (11), e79363
- https://doi.org/10.1371/journal.pone.0079363
Abstract
The Ca2+ 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 Ca2+ 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 Ca2+ affinity by 27% in the steady-state measurement and increased the Ca2+ 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 Ca2+ sensitivity due to the changes of the opening/closing equilibrium of cNTnC. In the skinned cardiomyocyte preparation, L29Q cTnC increased Ca2+ sensitivity in a highly sarcomere length (SL)-dependent manner. The well-established reduction of Ca2+ sensitivity by phosphomimetic cTnI was diminished by 68% in the presence of the mutation and it also depressed the SL-dependent increase in myofilament Ca2+ 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.Keywords
This publication has 62 references indexed in Scilit:
- The Role of Thin Filament Cooperativity in Cardiac Length-Dependent Calcium ActivationBiophysical Journal, 2010
- Myofilament length dependent activationJournal of Molecular and Cellular Cardiology, 2010
- Effect of Calcium-Sensitizing Mutations on Calcium Binding and Exchange with Troponin C in Increasingly Complex Biochemical SystemsBiochemistry, 2010
- A Functional and Structural Study of Troponin C Mutations Related to Hypertrophic CardiomyopathyPublished by Elsevier BV ,2009
- The cardiac troponin C mutation Leu29Gln found in a patient with hypertrophic cardiomyopathy does not alter contractile parameters in skinned murine myocardiumBasic Research in Cardiology, 2009
- Protein kinase A–dependent modulation of Ca2+ sensitivity in cardiac and fast skeletal muscles after reconstitution with cardiac troponinThe Journal of general physiology, 2009
- Challenging Current Paradigms Related to Cardiomyopathies: ARE CHANGES IN THE Ca2+ SENSITIVITY OF MYOFILAMENTS CONTAINING CARDIAC TROPONIN C MUTATIONS (G159D AND L29Q) GOOD PREDICTORS OF THE PHENOTYPIC OUTCOMES?Published by Elsevier BV ,2008
- GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular SimulationJournal of Chemical Theory and Computation, 2008
- Canonical sampling through velocity rescalingThe Journal of Chemical Physics, 2007
- VMD: Visual molecular dynamicsJournal of Molecular Graphics, 1996