Metabolism of Proteins

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DESCRIPTION (provided by applicant): Metabolism of proteins is highly regulated in physiological and pathophysiological states such as diabetes, starvation, etc. Both within the whole organism and at the cellular level, proteins exist in a dynamic state, maintained by the relative balance of protein synthesis and degradation. The bulk of cellular protein degradation is via the ubiquitin proteolytic pathway which provides both selectivity and specificity. Herein, cellular proteins via their internal lysine residues are tagged with ubiquitin and degraded via the proteasome. This pathway is responsible for the enhanced proteolysis of skeletal muscle in insulin-dependent diabetes and for the turnover of many regulatory molecules of metabolism including IRS-1 and IRS-2, key components of insulin action. Recent evidence suggests this pathway may exist within the cell nucleus. Our overall hypothesis is that cellular protein degradation is regulated in part by its loci of activity within the cell. In addition, recent data suggest a new targeting pathway for proteolysis with tagging via a protein's N terminus. The aims of the present proposal are thus (1) to analyze the motif, identify the components, and determine the physiological significance of N-terminus dependent ubiquitination of cellular proteins and (2) to define the subcellular sites and mechanisms responsible for protein degradation. These studies will be carried out using a variety of physiological, pharmacological, biochemical, molecular and cellular systems. Ultimately, the ability to modulate protein metabolism in physiological and pathophysiological states requires a detailed mechanistic understanding of the pathways of protein metabolism, the subject of the present proposal.