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- W2913865507 abstract "We have used electron paramagnetic resonance (EPR) spectroscopy to examine the protein-protein interaction of a recently discovered 34-codon micropeptide, dwarf open reading frame (DWORF), with the sarco/endoplasmic reticulum calcium ATPase (SERCA) in the presence and absence of phospholamban (PLB) in lipid vesicles. Heart failure is one of the leading causes of death in developed countries. A characteristic pathology of cardiac disease is inadequate activity of SERCA, the integral transmembrane Ca2+ pump, so SERCA activation is an important goal in developing treatments for heart failure. PLB is known to decrease SERCA's Ca2+ affinity through allosteric interactions. However, it has been shown that co-expression of DWORF with PLB and SERCA, in HEK293 cells, restores SERCA activity (Nelson et al., 2016). It has been proposed that this relief of SERCA inhibition is due to direct competition by DWORF for PLB binding to SERCA. To test this hypothesis in a membrane of defined protein and lipid composition, we co-reconstituted purified SERCA and spin-labeled PLB, with and without DWORF, in lipid vesicles. We then performed NADH-coupled Ca-ATPase assays to determine SERCA activity, and EPR experiments to determine the binding of PLB to SERCA. The sensitivity of EPR to structural dynamics, using stereospecifically attached spin labels, made the experiments extremely sensitive to PLB immobilization by SERCA. The results indicate that DWORF's restoration of SERCA activity correlates with some direct displacement of PLB from SERCA, but the fractional relief of inhibition exceeds the fractional PLB displacement, suggesting a more complex mechanism. These results provide direct insight of the equilibrium dynamics of SERCA and its regulators PLB and DWORF, providing valuable information for the development of novel therapeutic remedies for cardiac pathologies." @default.
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- W2913865507 date "2019-02-01" @default.
- W2913865507 modified "2023-10-18" @default.
- W2913865507 title "Electron Paramagnetic Resonance Elucidates the Structural Mechanism by Which SERCA is Activated by DWORF" @default.
- W2913865507 doi "https://doi.org/10.1016/j.bpj.2018.11.1539" @default.
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