ROLE OF THE C-TERMINAL REGION OF CARDIAC TROPONIN I IN THIN FILAMENT REGULATION

Zhiqun Zhou

Abnormal contraction and/or relaxation of cardiac muscle can cause heart diseases, heart failure, or even death. Contractile behavior of cardiac muscle is regulated by a series of Ca2+-induced structural transitions of troponin. These Ca2+-induced structural transitions regulate the alternating interactions between myosin heads and actin, but the detailed mechanisms of the regulation remain unclear. The long-term goal is to uncover the molecular basis of the Ca2+-induced protein structure transitions that underlie the regulation of cardiac function and to understand how these are altered in the diseased state. The overall objective of this work is to define the detailed dynamic and kinetic mechanisms of Ca2+-induced cardiac thin filament activation/deactivation, specific C-terminal of cTnI in the reconstituted preparations and determine how it is affected by troponin phosphorylation and cardiomyopathy mutations found in cTnI. The central hypothesis of this work is that different functional regions of cTnI play different roles in regulating dynamics and kinetics of the thin filament. We tested our hypothesis by monitoring the structural dynamic and kinetic transitions using various fluorescence spectroscopic techniques. Specific Aim 1 was designed to determine the dynamic and kinetic of each function region of C terminal of cTnI within reconstituted thin filament. Specific Aim 2 was designed to determine the structural and kinetic effects of selected hypertrophy cardiomyopathy (HCM) related cTnI mutations on the regulatory switching activity of cTnI within reconstituted thin filament. Specific Aim 3 was designed to determine the structural and kinetic effects of PKC-dependent phosphomimetic mutations on C-cTnI within reconstituted thin filament. Our findings reveal that each functional region of C-terminal of cTnI plays unique dynamic and kinetic roles in regulating Ca2+-induced crossbridge attachment/detachment; HCM-related mutations and PKC phosphomimetic mutations on C-cTnI modulate the dynamic and kinetic transitions in unique and various ways; the fly casting mechanism that normally underlies deactivation is preserved in spite of mutations. The positive impact of this work is that it provides a more detailed understanding of the mechanism of cardiac muscle regulation, which is important for understanding the molecular basis of disease-causing mutations and the possibility of rational therapeutic intervention.

ROLE OF THE C-TERMINAL REGION OF CARDIAC TROPONIN I IN THIN FILAMENT REGULATION

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