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In my laboratory, the primary research objective is to elucidate the structure of the myosin-containing thick filaments found in striated muscles. The goal of the work is to understand how differences in the packing of myosin and accessory proteins in thick filaments from different muscles may relate to differences in the physiological properties of the muscles and to understand the mechanism of force production at the molecular level. The key principle guiding much of the work is the observation from X-ray diffraction studies that the heads of the myosin molecules on the filament in living muscle are helically arranged. We have been one of the pioneering laboratories in the development of procedures which allow filaments from some muscles to be biochemically isolated with the helical arrangements of heads largely preserves, thus making the structure of the filaments amenable to analysis by a combination of electron microscopy with computer image analysis of the electron micrographs. This approach utilizes the principles of helical diffraction and computer image analysis of helical structures to determine the helical parameters and to compute a three-dimensional reconstruction of the electro density of the proteins in the thick filament.
Using this approach we have computed three-dimensional reconstructions both of several invertebrate (horseshoe crab and scorpion) and vertebrate (frog and fish) skeletal muscle thick filaments. The primary goal of the current research is to elucidate the structure of the mammalian cardiac muscle thick filament; and to study the effects of phosphorylation of myosin light chain and other thick filaments accessory proteins on the structure of the thick filaments and their interactions with actin to produce contraction. Determination of the structure of the cardiac thick filament as compared to the skeletal muscle thick filament is important for understanding the differences in physiological properties of cardiac muscle and skeletal muscle.
The techniques employed in the laboratory include electron microscopy (negative staining and platinum shadowing), computer image analysis both Fourier analysis and single particle analysis, cell fractionation, centrifugation, and SDS gel electrophoresis. Training opportunities are available for graduate students, undergraduates, and medical students.
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