The C-terminus of Troponin T Modulates Calcium Regulation of Actin-Myosin Interactions

Abstract

The highly conserved terminal fourteen C-terminal residues of troponin T play a novel role in the regulation of striated muscle contraction. Elimination of the terminal fourteen residues of the C-terminal region of troponin T stabilizes the functional active state and destabilizes one of two inactive states, the blocked state. We've used a series of functional assays to assess the magnitude of disruption to the actin state distribution by different mutations within that C-terminus. In doing so, we have identified the characteristics of the C-terminus required for its function. To probe the structural mechanism of the C-terminus of troponin T, we used a series of FRET pairs to measure the interactions of the C-terminus of troponin T and how those interactions are disrupted by C-terminal mutation. Though mutation in the C-terminus of troponin T is associated with a specific cardiovascular disease, hypertrophic cardiomyopathy, the findings from our lab indicate this region's function has broader implications on our fundamental understanding of striated muscle regulation and treatment of cardiovascular disease. Our incomplete understanding of this cycle's regulation has led to the generation of a variety of hypothesis to explain the gaps in our knowledge. We have taken steps to characterize the functional and structural consequence of mutation within the C-terminus of troponin T and now believe we have closed some of the gaps in our knowledge of this regulated cycle.