Publications by authors named "Colleen M Kelly"

The polymerization of myosin molecules into thick filaments in muscle sarcomeres is essential for cardiac contractility, with the attenuation of interactions between the heads of myosin molecules within the filaments being proposed to result in hypercontractility, as observed in hypertrophic cardiomyopathy (HCM). However, experimental evidence demonstrates that the structure of these giant macromolecular complexes is highly dynamic, with molecules exchanging between the filaments and a pool of soluble molecules on the minute timescale. Therefore, we sought to test the hypothesis that the enhancement of interactions between the heads of myosin molecules within thick filaments limits the mobility of myosin by taking advantage of mavacamten, a small molecule approved for the treatment of HCM.

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Rationale: Cardiac muscle cells are terminally differentiated after birth and must beat continually throughout one's lifetime. This mechanical process is driven by the sliding of actin-based thin filaments along myosin-based thick filaments, organized within sarcomeres. Despite costly energetic demand, the half-life of the proteins that comprise the cardiac thick filaments is ∼10 days, with individual molecules being replaced stochastically, by unknown mechanisms.

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Myosin and myosin-binding protein C are exquisitely organized into giant filamentous macromolecular complexes within cardiac muscle sarcomeres, yet these proteins must be continually replaced to maintain contractile fidelity. The overall hypothesis that myosin filament structure is dynamic and allows for the stochastic replacement of individual components was tested in vivo, using a combination of mass spectrometry- and fluorescence-based proteomic techniques. Adult mice were fed a diet that marked all newly synthesized proteins with a stable isotope-labeled amino acid.

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Titin is a large filamentous protein that spans half a sarcomere, from Z-disk to M-line. The N2A region within the titin molecule exists between the proximal immunoglobulin (Ig) region and the PEVK region and protein-protein interactions involving this region are required for normal muscle function. The N2A region consists of four Ig domains (I80-I83) with a 105 amino acid linker region between I80 and I81 that has a helical nature.

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