Characterization of the conformational states of phospholamban and their roles in regulation of SR Calcium-ATPase
2012-12
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Characterization of the conformational states of phospholamban and their roles in regulation of SR Calcium-ATPase
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2012-12
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Membrane proteins constitute 30% of the human genome but represent only a small fraction of the known three-dimensional protein structures. In this thesis I describe the characterization of the membrane protein complex between sarcoplasmic reticulum Ca2+-ATPase (SERCA) and phospholamban (PLN). SERCA drives cardiac muscle relaxation by active transport of Ca2+ ions into the SR. PLN is a small membrane protein that consists of a helical trans-membrane domain connected to a cytoplasmic domain through a short loop, and inhibits SERCA through intra-membrane interactions. The cytoplasmic domain of PLN is in equilibrium between a helical, membrane-associated T state and an unfolded, membrane-dissociated R state. Here, I summarize the work to probe the structures of the T and R states and elucidate the role of the conformational equilibrium in regulation of SERCA. Using solution and solid state NMR in combination with biochemical assays I show that the structures of T and R state but not their relative populations are conserved in different lipid environments and sample conditions. Furthermore, the T/ R equilibrium has a central role in SERCA regulation and is crucial to relieve the inhibition of the enzyme. These findings provide new insights into SERCA/PLN function and offer a unique view of the role of conformational equilibria and multiple conformational states in membrane protein structure and function.
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University of Minnesota Ph.D. dissertation. December 2012. Major: Biochemistry, Molecular Bio, and Biophysics. Advisor: Dr. Gianluigi Veglia. ix, 262 pages.
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Gustavsson, Bengt Martin. (2012). Characterization of the conformational states of phospholamban and their roles in regulation of SR Calcium-ATPase. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/171109.
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