Regulated proteolysis by the ubiquitin-proteasome system (ubiquitin system) plays essential roles in a multitude of biological processes, and has major ramifications for human health. Our studies of the ubiquitin system and the N-end rule pathway over the last three decades were made possible, to a large extent, by the present grant (DK039520), currently in its 27th year of support. This renewal application is about the N-end rule pathway of protein degradation. In eukaryotes, this pathway is a specific part of the ubiquitin system. The N-end rule relates the in vivo half-life of a protein to the identity of its -terminal residue. The N-end rule pathway of protein degradation consists of two distinct branches, the Ac/N-end rule pathway and the Arg/N-end rule pathway. The Ac/N-end rule pathway was discovered by our laboratory in 2010. It recognizes proteins with N-terminally acetylated residues. The Arg/N-end rule pathway, which targets specific unacetylated N-terminal residues, was discovered by our laboratory in 1986. This pathway continues to be a fount of biological insights and remains a major focus of our studies. The present (DK039520) renewal application is about the Arg/N-end rule pathway and the identification (as well as detailed studies) of new physiological Arg/N-rule substrates. Therefore the previous title of the DK039520 grant (Ubiquitin Ligases, Mechanisms and Functions of the N-End Rule Pathway) was modified as follows in the present renewal application, to reflect its current emphasis: The Mammalian Arg/N-End Rule Pathway: Substrates, Functions, and Mechanisms. The projects of this renewal application include functional and mechanistic studies of specific physiological substrates of the mammalian (mouse) Arg/N-end rule pathway, and the identification of new mammalian Arg/N-end rule substrates, including those that act as proapoptotic protein fragments, i.e., fragments whose formation during apoptosis (a specific kind of programmed cell death) increases the probability of apoptosis.
Studies proposed in this renewal application for the DK039520 grant will address the functions of regulated protein degradation in mammalian cells. Inborn or acquired defects in proteolytic systems, which include the ubiquitin system, are a major cause of many human diseases, including cancer, infections, and neurodegenerative syndromes. Understanding the functions and mechanisms of the ubiquitin-dependent N-end rule pathway, a focus of our studies, contributes to advances in fundamental biology, and is also likely to lead to better therapies for specific medical problems, including currently intractable ones.
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