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Browsing by Author "Mote, Kaustubh"

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    Structural Characterization of Sarcolipin by Solid State NMR and Investigation of its Role in the Regulation of Sarco(endo)plasmic Reticulum Calcium Adenosine-Triphospatase
    (2014-02) Mote, Kaustubh
    Structural characterization of membrane proteins and their complexes is an important and ever growing challenge to the classical techniques of biomolecular structural characterization. Rapid developments in the field of solid state NMR (ssNMR) have opened up an exciting new alternative to X-ray crystallography, as these studies can now be performed in fully hydrated lipid bilayers that faithfully mimic the physiologically relevant conditions. Nonetheless, routine application of ssNMR on biomolecular systems is hampered by their low sensitivity and spectral resolution. In this work, we have addressed these challenges by developing new strategies to study membrane proteins by ssNMR. With a set of improved pulse sequences for oriented and magic angle spinning techniques in ssNMR, we determined the topology (i.e. the structure and transmembrane orientation) of sarcolipin, a regulator of the Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA), in lipid bilayers. These techniques are further used to study the complex between these two proteins and understand the molecular basis for this regulatory interaction. The methodological developments reported here are transferable to studies on other membrane proteins and they clear several roadblocks in the successful application of ssNMR for these challenging bio-molecular systems. Finally, we present how these studies have furthered our understanding of the regulation of muscle relaxation process by SERCA. These findings represent the first steps in designing new therapeutic approaches for cardiac and skeletal muscle disorders.