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Principal Investigator: ALEXANDER J VARSHAVSKY
Organization: CALIFORNIA INSTITUTE OF TECHNOLOGY
Fiscal Year: 2024
Award: $575,028
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary/Abstract
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 and disease, including
illnesses that range from cancer and neurodegeneration to cardiovascular syndromes and defects of
immunity. Our studies of the ubiquitin-proteasome system and ubiquitin-dependent N-degron pathways
(previously called “N-end rule pathways”) over more than three decades were made possible, to a large
extent, by the present grant (DK039520), currently in its 34th year of support. N-degron pathways
recognize proteins containing N-terminal (Nt) degradation signals called N-degrons, polyubiquitylate these
proteins and thereby cause their degradation by the proteasome or autophagy. Recognition components of
N-degron pathways, called N-recognins, are E3 ubiquitin ligases that can target N-degrons. One eukaryotic
N-degron pathway, called the Arg/N-degron pathway, targets, in particular, specific unmodified Nt-residues
of protein substrates. Another Nt-proteolytic system, called the Pro/N-degron pathway, recognizes, in
particular, the Nt-proline (Pro) residue of protein substrates.
This DK039520 renewal application stems from our unpublished studies over the last ~2 years, and
focuses on the yeast (S. cerevisiae) Pro/N-degron and Arg/N-degron pathways, including the functions of
specific aminopeptidases and the recently discovered ability of Ubr1, the E3 of the Arg/N-degron pathway,
to target not only N-degrons but also C-degrons. These and related studies, described in Specific Aims of
the DK039520 renewal application, will advance the understanding of protein degradation and the
universally present (as well as medically significant) N-degron pathways.
Terms: <20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome><APF-1><ATP-Dependent Proteolysis Factor 1><Acetylation><Amino Acids><Aminopeptidase><Aminopeptidase A><Angiotensinase A><Animals><Apoptosis><Apoptosis Pathway><Aspartate Aminopeptidase><Aspartyl Aminopeptidase><Autophagocytosis><Baker's Yeast><Biological Function><Biological Process><Biology><Brewer's Yeast><C-terminal><Ca2+-Activated Protease><Calcium-Activated Neutral Protease><Calcium-Activated Neutral Proteinase><Calcium-Activated Protease><Calcium-Dependent Neutral Protease><Calcium-Dependent Neutral Proteinase><Calpain><Cancers><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Caspase><Caspase Gene><Cathepsins><Cell Body><Cell Communication and Signaling><Cell Cycle><Cell Differentiation><Cell Differentiation process><Cell Division Cycle><Cell Locomotion><Cell Migration><Cell Movement><Cell Nucleus><Cell Signaling><Cell-Death Protease><Cells><Cellular Migration><Cellular Motility><Chaperone><Chromosome Cohesion><Circadian Rhythms><Cysteine Endopeptidases><Cysteine Protease><Cysteine Proteinases><Cytoskeletal Gene><Cytoskeletal Proteins><Cytosol><DNA Damage Repair><DNA Repair><Defect><Desminase><Disease><Disorder><E3 Ligase><E3 Ubiquitin Ligase><Endogenous Nitrate Vasodilator><Endothelium-Derived Nitric Oxide><Enzyme Gene><Enzymes><Esteroproteases><Eukaryotic Cell><Ferroprotoporphyrin><G-Proteins><GTP-Binding Proteins><GTP-Regulatory Proteins><Gene Transcription><Genes><Genetic Code><Genetic Transcription><Gluconeogenesis><Grant><Guanine Nucleotide Coupling Protein><Guanine Nucleotide Regulatory Proteins><HMG-20><Health><Heart Vascular><Heme><High Mobility Protein 20><Human><ICE-like protease><Immune system><Immunity><Infection><Inflammation><Innate Immunity><Intracellular Communication and Signaling><Kinases><L-Proline><Laboratories><Length><Link><Macropain><Macroxyproteinase><Malignant Neoplasms><Malignant Tumor><Mammalia><Mammals><Mediating><Medical><Meiosis><Metabolic Protein Degradation><Mitosis Checkpoint><Mitotic Checkpoint><Modern Man><Molecular Chaperones><Mononitrogen Monoxide><Multicatalytic Proteinase><N-terminal><NH2-terminal><Names><Native Immunity><Natural Immunity><Nerve Degeneration><Neuron Degeneration><Nitric Oxide><Nitrogen Monoxide><Nitrogen Protoxide><Non-Specific Immunity><Nonspecific Immunity><Nucleus><Nyctohemeral Rhythm><O element><O2 element><Oxygen><Papain-Like Cysteine Protease><Pathway interactions><Peptidases><Peptide Hydrolases><Peptide Transport><Phosphotransferase Gene><Phosphotransferases><Physiologic><Physiological><Plants><Play><Process><Programmed Cell Death><Progress Reports><Proline><Prosome><Protease Gene><Proteases><Proteasome><Proteasome Endopeptidase Complex><Protein Cleavage><Protein Turnover><Proteinases><Proteins><Proteolysis><Proteolytic Enzymes><Proteosome><Protoheme><RNA Expression><Regulation><Regulatory Protein Degradation><Research><Role><Route><S cerevisiae><S. cerevisiae><Saccharomyces cerevisiae><Semantics><Signal Transduction><Signal Transduction Systems><Signaling><Spermatogenesis><Syndrome><System><Terminology><Transcription><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Translations><Transphosphorylases><Twenty-Four Hour Rhythm><Ubiquitin><Ubiquitin Ligase Component Gene><Ubiquitin Ligase Gene><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><Unscheduled DNA Synthesis><Work><Yeasts><aberrant folded protein><aberrant folded proteins><abnormal folded protein><abnormal folded proteins><adaptive immunity><aminoacid><autophagy><biological adaptation to stress><biological signal transduction><cell motility><cellular differentiation><circadian process><circulatory system><cystein protease><cystein proteinase><cysteine endopeptidase><daily biorhythm><deamidation><endothelial cell derived relaxing factor><fat metabolism><ferroheme><fungus><glucose biosynthesis><glutamyl aminopeptidase><human disease><in vivo><lipid metabolism><malignancy><meiotic><misfolded protein><misfolded proteins><mitosis check point><mitotic check point><multicatalytic endopeptidase complex><name><named><naming><neoplasm/cancer><neural degeneration><neurodegeneration><neurodegenerative><neurogenesis><neurological degeneration><neuronal degeneration><oxidation><pathway><protein complex><protein degradation><proteotoxic protein><proteotoxin><reaction; crisis><recognins><segregation><separase><separin><social role><stem><stoichiometry><stress response><stress; reaction><translation><ubiquitin ligase><ubiquitin-protein ligase>