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Principal Investigator: JOAN M HEVEL
Organization: UTAH STATE UNIVERSITY
Fiscal Year: 2024
Award: $90,241
Funding agency: National Institute of General Medical Sciences
PROJECT SUMMARY
Protein arginine methylation catalyzed by Protein arginine methyltransferase 1 (PRMT1) is of
intense current interest as an anti-cancer therapeutic target, as well as a mediator of lung, kidney,
neurodegenerative and cardiovascular pathologies. To date, the majority of studies
characterizing the consequences of PRMT1-mediated protein methylation have not considered
the biochemical mechanisms by which PRMT1 activity is altered, which is pivotal in understanding
how PRMT1 participates in cellular homeostasis, the progression of the aforementioned disease
states, and in developing treatment protocols to control PRMT1-dependent cellular events. The
two hypotheses being tested in this project are: 1) changes in oligomeric state and site-specific
cysteine oxidation of the PRMT1 protein affect substrate targeting and activity, and 2) that a
cysteine residue in PRMT1 can be harnessed to create/upgrade isoform-specific PRMT1
inhibitors. In Aim 1, novel fluorescence-based biophysical methods will be used to characterize
the dynamics of PRMT1 oligomer formation in intact cells. Strategically designed variants of
PRMT1 which present as tetramers, dimers, or monomers will be used to identify binding and
catalytic differences in the targeting by each oligomer, aiding in the ongoing effort to understand
molecular recognition rules of PRMT1 for its substrates. The effect of sulfenylation at a cysteine
residue near the active site of PRMT1 will also be characterized, allowing for the development of
stable oxidized and reduced mimics of PRMT1 to be used as research tools in areas of human
health affected by oxidative stress. The objectives in Aim 1 are built upon initial in vitro findings
by the PI and are expected to apply to the long-term goal of characterizing mechanisms of
regulating PRMT1 activity in vivo. In Aim 2, the strategy of using a nucleophilic cysteine near the
active site of PRMT1 to enable covalent inhibition by adenosine derivatives will be explored. This
strategy would be a valuable way to salvage inhibitors that show a lack of isoform-specificity, but
otherwise perform well to inhibit PRMT activity. Covalent inhibitors represent a novel, rationale
avenue for developing PRMT1 drugs and research tools. Undergraduate and graduate
researchers with interests in future careers in biomedical research or medicine will be involved in
the project and receive training in experimental design and analysis, notebook keeping, scientific
writing and presentation.
Terms: <Active Sites><Adenosine><Administrative Supplement><Affect><Area><Arginine><Arginine Methylase><Autoregulation><Binding><Biochemical><Biochemistry><Biological><Biological Chemistry><Biomedical Research><Cancer Induction><Cardiovascular Diseases><Cardiovascular Pathology><Catalysis><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Cycle Control><Cell Cycle Regulation><Cell Extracts><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Chemistry><Chronic Disease><Chronic Illness><Communication><Cysteine><DNA Damage Repair><DNA Repair><Degenerative Neurologic Disorders><Development><Disease><Disease Progression><Disorder><Drugs><Enzyme Gene><Enzymes><Estrogen Receptors><Eukaryotic Cell><Event><Experimental Designs><Family><Fluorescence><Future><Goals><Grouping><Half-Cystine><Health><Histone (Arginine) Methyltransferase><Histone H4><Histones><Homeostasis><Human><In Vitro><Inflammatory><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Investigators><Isoforms><Kidney><Kidney Diseases><Kidney Urinary System><Kinetics><L-Arginine><L-Cysteine><Lung><Lung Diseases><Lung Respiratory System><Mammalian Cell><Mediating><Mediator><Medication><Medicine><Methylation><Modern Man><Modification><Molecular Interaction><Myelin Basic Protein (Arginine) Methyltransferase><N,N-dimethylarginine><NIH><National Institutes of Health><Nephropathy><Nerve Degeneration><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neuron Degeneration><Oxidative Stress><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Physiological Homeostasis><Play><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Progesterone Receptors><Progestin Receptors><Protein Arginine Methyltransferase><Protein Dynamics><Protein Inhibition><Protein Isoforms><Protein Methylase I><Protein Methylation><Protein Methyltransferase I><Protein Modification><Protein-Arginine N-Methyltransferase><Proteins><Pulmonary Diseases><Pulmonary Disorder><Regulation><Renal Disease><Research><Research Personnel><Researchers><Role><Signal Transduction><Signal Transduction Systems><Signaling><Site><Specificity><Spectroscopy><Spectrum Analyses><Spectrum Analysis><Stress><Subcellular Process><Testing><Training><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Translations><Treatment Protocols><Treatment Regimen><Treatment Schedule><United States National Institutes of Health><Universities><Unscheduled DNA Synthesis><Utah><Variant><Variation><Viral Pathogenesis><Work><Writing><anti-cancer therapeutic><asymmetric dimethylarginine><biologic><biological signal transduction><biophysical approaches><biophysical methodology><biophysical methods><biophysical techniques><carcinogenesis><cardiovascular disorder><career><cell culture><cell cultures><chemical reaction><chronic disorder><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><design><designing><developmental><dimer><dimethyl-L-arginine><dimethylarginine><disease of the lung><disorder of the lung><drug development><drug/agent><enthusiastic atmosphere><enthusiastic environment><epigenetic regulation><equipment acquirement><equipment acquisition><equipment investment><equipment procurement><equipment purchase><equipment purchasing><experimental analysis><graduate student><groupings><guanidino-N,N-dimethylarginine><in vivo><inhibit protein><inhibit proteins><inhibitor><instrument acquisition><instrument investment><instrument procurement><instrument purchase><interest><interventional strategy><kidney disorder><lung disorder><molecular recognition><monomer><neural degeneration><neurodegeneration><neurodegenerative><neurodegenerative illness><neurological degeneration><neuronal degeneration><non-histone protein><nonhistone protein><novel><oxidation><pharmaceutical><programs><protein function><protein inhibitions><pulmonary><renal><renal disorder><small molecule><social role><supportive atmosphere><supportive environment><therapeutic target><tool><translation><undergrad><undergraduate><undergraduate research><undergraduate student><virus pathogenesis>