Browsing by Subject "Nuclear Magnetic Resonance"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Mechanism of Phospholamban Activation by HAX-1 and their Roles in the Regulation of the SR Calcium-ATPase
    (2021-04) Larsen, Erik
    The Ca2+ transient of the cardiomyocyte is key to the contractility of the heart. Its dysregulation has been associated with heart disease, leading to investigation of the regulation of Ca2+ for potential drug targets. The Sarcoplasmic Endo-Reticulum Ca2+ ATP-ase (SERCA) pump and its main inhibitor in heart tissue, phospholamban (PLN), are two promising targets that are under β-adrenergic control via phosphorylation of PLN by Protein Kinase A (PKA). Phosphorylation of Ser16 on the cytoplasmic domain of PLN results in decreased inhibition of SERCA. Recently, an additional member of the SERCA interactome has been discovered called Hematopoietic lineage cell-specific protein 1 (HCLS1) Associated Protein X-1 (HAX-1). Contrasting PLN phosphorylation, the interaction of HAX-1 and PLN increases the inhibition of PLN for SERCA, adding another layer of complexity to SERCA regulation and a potential new drug target. This thesis aims to investigate the structure-function relationship of the ternary complex, SERCA/PLN/HAX-1 using NMR spectroscopy as the primary technique.
  • Thumbnail Image
    Item
    Towards the full molecular investigation of protein kinase a mediated catalysis by NMR spectroscopy.
    (2009-03) Masterson, Larry Raou
    The reversible phosphorylation of proteins is fundamental to the modulation of myocardial contraction. A mechanism which controls this modulation occurs through alterations of Ca2+ flux formed across the sarcoplasmic reticulum (SR) membrane inside cardiomyocytes. Changes in this flux have a profound dependence on the interactions of three proteins: protein kinase A (PKA), sarcoendoplasmic reticulum Ca2+-ATPase (SERCA), and phospholamban (PLN). Phosphorylation of PLN by PKA is associated with an augmented rate of SR Ca2+ uptake and relaxation of the myocardium. Mutants of PLN (R9C-PLN and R14Del-PLN) have previously been shown to be linked with forms of the fatal hereditary disease, dilated cardiomyopathy. The molecular basis of disease in this situation could result from irregularities in the association of these PLN mutants with PKA. The work presented here lays the foundation for obtaining the molecular details which govern these interactions to further our understanding of the processes which control Ca2+ transport in myocytes and, perhaps, lend insight into the origins of this disease.