Structures and interactions of tropomyosin with caldesmon and troponin


Tropomyosin plays a central role in the regulation of skeletal, cardiac, and smooth muscle regulation. The regulatory properties of tropomyosin are mediated by its interactions with muscle-specific tropomyosin binding proteins. In skeletal and cardiac muscle the regulatory protein is troponin, while in smooth muscle the primary protein is caldesmon. The structures and interactions of tropomyosin with caldesmon, skeletal troponin, and cardiac troponin have been studied using X-ray crystallography and optical biosensors. Only whole caldesmon and the carboxyl-terminal domain of caldesmon bound tightly to tropomyosin. X-ray studies showed that whole caldesmon bound to tropomyosin in several places. Experiments with the carboxyl-terminal domain of caldesmon revealed that this region corresponded to the strongest binding site seen for whole caldesmon. Weaker association of other regions of caldesmon to tropomyosin was also observed. The structure of cocrystals of skeletal and cardiac troponin subunit T revealed that the two isoforms interacted with tropomyosin in the same general area but that cardiac troponin T bound to tropomyosin over a more extended region. The longer amino-terminal domain of the cardiac protein bound further along the carboxyl region of tropomyosin than skeletal troponin T, and the carboxyl-terminal domain of cardiac troponin T bound to tropomyosin more tightly than its skeletal counterpart. Biosensors studies of tropomyosin interacting with caldesmon and troponin measured association rate, dissociation rate, and equilibrium rate constants of these proteins for the first time. Caldesmon bound with similar affinity to several tropomyosin isoforms while troponin bound most tightly to striated muscle tropomyosin. An atomic model of tropomyosin at 5 A resolution has been constructed using a simulated annealing procedure and X-ray diffraction data from the spermine crystal form of tropomyosin. During these refinements the R-free and R were monitored. However, failure to lower the R-free suggests that this model does not accurately describe the structure of tropomyosin within these crystals. These results define interactions and structures within thin filaments of cardiac, skeletal, and smooth muscle which will be useful in elucidating the exact role of these proteins in the unique regulation of each type of muscle

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This paper was published in DSpace at Rice University.

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