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Principal Investigator: Jiaoyang Jiang
Organization: UNIVERSITY OF WISCONSIN-MADISON
Fiscal Year: 2024
Award: $397,900
Funding agency: National Institute of General Medical Sciences
Abstract
The essential human enzyme O-GlcNAc transferase (OGT) catalyzes a unique type of intracellular protein
glycosylation called O-GlcNAcylation. In response to nutrient levels and stress, OGT dynamically regulates a
variety of physiological and pathological processes including the “Warburg effect” in cancer cells and insulin
resistance in diabetes. Previous studies on the OGT active site have made fundamental discoveries on its
catalytic mechanism and substrate interactions. However, how OGT regulates protein- and site-specific O-
GlcNAcylation remains unclear. This is due to a number of challenges including: 1) OGT glycosylates thousands
of proteins without a conserved sequence motif near the O-GlcNAc modification site, 2) a majority of O-
GlcNAcylation sites are found on intrinsically disordered regions (IDRs), 3) OGT typically binds proteins with
low/moderate affinity, and 4) a lack of OGT-protein complex structures. In our last funding period, we have made
strides in these areas through development of a suite of novel chemical probes that allow us to interrogate OGT
specific interactions with low/moderate affinity for structural, proteomic, and biochemical characterizations. This
proposal aims to make further conceptual and technical breakthroughs toward addressing these longstanding
challenges. It is expected that a better understanding of how OGT interacts with other proteins, particularly
through the regions beyond the OGT catalytic site, will be essential for understanding OGT’s functional regulation
at protein- and site-specific levels, filling major knowledge gaps between decades of biological observations of
OGT’s nutrient sensing and other regulatory roles, and will support the need to specifically modulate OGT
functions for biomedical applications.
Terms: <Active Sites><Address><Affinity><Area><Assay><Binding><Binding Proteins><Binding Site Domain><Binding Sites><Bioassay><Biochemical><Biological><Biological Assay><Biology><Cancers><Catalytic Core><Catalytic Domain><Catalytic Region><Catalytic Site><Catalytic Subunit><Cell Body><Cells><Chemicals><Combining Site><Complex><Conserved Sequence><Coupled><Coupling><Development><Diabetes Mellitus><Disease><Disorder><Enzyme Gene><Enzyme Kinetics><Enzymes><Funding><Genetic Alteration><Genetic Change><Genetic defect><Human><In Vitro><Insulin Resistance><Investigation><Knowledge><Ligand Binding Domain><Ligand Binding Protein><Ligand Binding Protein Gene><Link><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Mediating><Metabolic Glycosylation><Modern Man><Modification><Molecular><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Mutation><Nutrient><O-GlcNAc Transferase gene><O-GlcNAc transferase><Organism-Level Process><Organismal Process><Outcome><Pathologic Processes><Pathological Processes><Pathway interactions><Peptides><Phage Display><Physiologic Processes><Physiological Processes><Protein Binding><Protein Glycosylation><Proteins><Proteome><Proteomics><Reactive Site><Regulation><Research><Resolution><Role><Scaffolding Protein><Site><Stress><Structure><Substrate Interaction><System><Techniques><Time><Warburg Effect><biologic><bound protein><cancer cell><conformation><conformational><conformational state><conformationally><conformations><detection of nutrient><developmental><diabetes><drug discovery><experiment><experimental research><experimental study><experiments><genome mutation><glycosylation><imaging approach><imaging based approach><innovate><innovation><innovative><insight><insulin resistant><insulin tolerance><interest><malignancy><mutant><neoplasm/cancer><novel><nutrient sensing><pathway><perception of nutrients><protein complex><protein protein interaction><resolutions><response><sensor><social role><structural biology><sugar>