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dc.contributor.authorDillon, Myles B.C.
dc.contributor.authorRust, Heather L.
dc.contributor.authorThompson, Paul R
dc.contributor.authorMowen, Kerri A.
dc.date2022-08-11T08:11:00.000
dc.date.accessioned2022-08-23T17:28:07Z
dc.date.available2022-08-23T17:28:07Z
dc.date.issued2013-09-27
dc.date.submitted2015-05-22
dc.identifier.citationJ Biol Chem. 2013 Sep 27;288(39):27872-80. doi: 10.1074/jbc.M113.491092. Epub 2013 Aug 14. <a href="http://dx.doi.org/10.1074/jbc.M113.491092">Link to article on publisher's site</a>
dc.identifier.issn0021-9258 (Linking)
dc.identifier.doi10.1074/jbc.M113.491092
dc.identifier.urihttp://hdl.handle.net/20.500.14038/50011
dc.description<p>At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.</p>
dc.description.abstractProtein arginine methyltransferase (PRMT) 8 is unique among the PRMTs, as it has a highly restricted tissue expression pattern and an N terminus that contains two automethylation sites and a myristoylation site. PRMTs catalyze the transfer of a methyl group from S-adenosylmethionine (AdoMet) to a peptidylarginine on a protein substrate. Currently, the physiological roles, regulation, and cellular substrates of PRMT8 are poorly understood. However, a thorough understanding of PRMT8 kinetics should provide insights into each of these areas, thereby enhancing our understanding of this unique enzyme. In this study, we determined how automethylation regulates the enzymatic activity of PRMT8. We found that preventing automethylation with lysine mutations (preserving the positive charge of the residue) increased the turnover rate and decreased the Km of AdoMet but did not affect the Km of the protein substrate. In contrast, mimicking automethylation with phenylalanine (i.e. mimicking the increased hydrophobicity) decreased the turnover rate. The inhibitory effect of the PRMT8 N terminus could be transferred to PRMT1 by creating a chimeric protein containing the N terminus of PRMT8 fused to PRMT1. Thus, automethylation of the N terminus likely regulates PRMT8 activity by decreasing the affinity of the enzyme for AdoMet.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=23946480&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784702/
dc.subjectCatalysis
dc.subjectHeLa Cells
dc.subjectHumans
dc.subjectLysine
dc.subjectMembrane Proteins
dc.subjectMethylation
dc.subjectMutagenesis, Site-Directed
dc.subjectMutation
dc.subjectPhenylalanine
dc.subjectProtein Binding
dc.subject*Protein Processing, Post-Translational
dc.subjectProtein Structure, Tertiary
dc.subjectProtein-Arginine N-Methyltransferases
dc.subjectS-Adenosylmethionine
dc.subjectBiochemistry
dc.subjectEnzymes and Coenzymes
dc.subjectMedicinal-Pharmaceutical Chemistry
dc.subjectTherapeutics
dc.titleAutomethylation of protein arginine methyltransferase 8 (PRMT8) regulates activity by impeding S-adenosylmethionine sensitivity.
dc.typeJournal Article
dc.source.journaltitleThe Journal of biological chemistry
dc.source.volume288
dc.source.issue39
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/thompson/22
dc.identifier.contextkey7135673
html.description.abstract<p>Protein arginine methyltransferase (PRMT) 8 is unique among the PRMTs, as it has a highly restricted tissue expression pattern and an N terminus that contains two automethylation sites and a myristoylation site. PRMTs catalyze the transfer of a methyl group from S-adenosylmethionine (AdoMet) to a peptidylarginine on a protein substrate. Currently, the physiological roles, regulation, and cellular substrates of PRMT8 are poorly understood. However, a thorough understanding of PRMT8 kinetics should provide insights into each of these areas, thereby enhancing our understanding of this unique enzyme. In this study, we determined how automethylation regulates the enzymatic activity of PRMT8. We found that preventing automethylation with lysine mutations (preserving the positive charge of the residue) increased the turnover rate and decreased the Km of AdoMet but did not affect the Km of the protein substrate. In contrast, mimicking automethylation with phenylalanine (i.e. mimicking the increased hydrophobicity) decreased the turnover rate. The inhibitory effect of the PRMT8 N terminus could be transferred to PRMT1 by creating a chimeric protein containing the N terminus of PRMT8 fused to PRMT1. Thus, automethylation of the N terminus likely regulates PRMT8 activity by decreasing the affinity of the enzyme for AdoMet.</p>
dc.identifier.submissionpaththompson/22
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.source.pages27872-80


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