Class
Article
College
College of Science
Department
Chemistry and Biochemistry Department
Faculty Mentor
Joan Hevel
Presentation Type
Poster Presentation
Abstract
Communication within and between cells, either in the context of normal biological activities or in response to stressors or other stimuli, is a crucial aspect of cell function. One strategy parts of a cell uses to communicate with other parts involves protein arginine methylation. This is a post-translational modification that is catalyzed by the members of the Protein Arginine Methyltransferase (PRMT) family of enzymes. PRMTs are ubiquitous in eukaryotic organisms and they are involved in many signaling pathways in many tissues. Given this broad activity, along with the fact that aberrant arginine methylation is associated with a variety of life-threatening diseases, one might expect that the PRMTs are tightly regulated. However despite decades of research, mechanisms that regulate the PRMTs and the processes that lead to PRMT dysregulation are not well understood. It is widely believed, however, that dimerization is essential for PRMT activity. Studies in PRMT1 have shown that perturbation of the PRMT1 dimer arm abolishes PRMT1 activity. Here we discuss some of our results from a biochemical characterization of three naturally occurring PRMT1 dimer arm mutations (W197L, Y202N, M206V), which have been detected in human cancers. A construct harboring all three mutations is monomeric and inactive. Subsequent analysis of the single mutant constructs indicates that dimerization and oligomerization is disrupted, but not abolished in each of these constructs, and all three constructs show significantly decreased activity compared to wild type. Further biochemical and computational analysis of these mutants constructs will provide insights to the underlying mechanistic role of dimer and oligomer formation in PRMT1. The critical role of PRMT1 in maintaining cellular health coupled with the observation that each of these mutations occurs in cancer cells and disrupt activity provides a clear rationale for their likely contribution to disease pathology. Presentation Time: Wednesday, 1-2 p.m.
Location
Logan, UT
Start Date
4-11-2021 12:00 AM
Included in
Use of Cancer-Associated Mutations to Probe the Role of Dimerization in Protein Arginine Methyltransferase 1 Catalysis and Physiological Dysfunction
Logan, UT
Communication within and between cells, either in the context of normal biological activities or in response to stressors or other stimuli, is a crucial aspect of cell function. One strategy parts of a cell uses to communicate with other parts involves protein arginine methylation. This is a post-translational modification that is catalyzed by the members of the Protein Arginine Methyltransferase (PRMT) family of enzymes. PRMTs are ubiquitous in eukaryotic organisms and they are involved in many signaling pathways in many tissues. Given this broad activity, along with the fact that aberrant arginine methylation is associated with a variety of life-threatening diseases, one might expect that the PRMTs are tightly regulated. However despite decades of research, mechanisms that regulate the PRMTs and the processes that lead to PRMT dysregulation are not well understood. It is widely believed, however, that dimerization is essential for PRMT activity. Studies in PRMT1 have shown that perturbation of the PRMT1 dimer arm abolishes PRMT1 activity. Here we discuss some of our results from a biochemical characterization of three naturally occurring PRMT1 dimer arm mutations (W197L, Y202N, M206V), which have been detected in human cancers. A construct harboring all three mutations is monomeric and inactive. Subsequent analysis of the single mutant constructs indicates that dimerization and oligomerization is disrupted, but not abolished in each of these constructs, and all three constructs show significantly decreased activity compared to wild type. Further biochemical and computational analysis of these mutants constructs will provide insights to the underlying mechanistic role of dimer and oligomer formation in PRMT1. The critical role of PRMT1 in maintaining cellular health coupled with the observation that each of these mutations occurs in cancer cells and disrupt activity provides a clear rationale for their likely contribution to disease pathology. Presentation Time: Wednesday, 1-2 p.m.