Joan M. Hevel
Click hereto view webpage.
B.S., 1988, Lebanon Valley College
Ph.D., 1993, University of Michigan
Postdoctoral, 1993-1996, University of California, Berkeley
Postdoctoral, 1997-1999, University of Hawaii, Manoa
Postdoctoral & Instructor, 2000-2003, University of South Alabama
At the heart of all protein functions, whether they are enzymatic or structural, is protein structure. In turn, the function of individual proteins can be altered by small molecules, covalent modifications, and protein-protein interactions. This makes ascribing function to the vast proteome even more daunting. Since protein-protein and protein-DNA interactions are vital for a multitude of mammalian cellular processes, understanding the determinants for binding, the potential structural and functional changes in each protein, and the function of the resultant complex is fundamental to not only understanding basal cellular communication but also what happens when the cellular environment deviates as in a disease state, stress, or cancer. Our group is interested in studying how protein structure is utilized by a cell to communicate a particular response. Summarized below are two systems we are using to gain a better understanding of how protein structures govern function.
The Bi-Functional Proteins DCoH and DCoHα
DCoH and DCoHα are mammalian bi-functional proteins that act both as enzymes to dehydrate 4a-hydroxy-tetrahydrobiopterin and as coactivators of transcription by complexing with the transcription factor HNF1α. Mutations in these proteins have been associated with hyperphenylalaninemia and diabetes, respectively. HNF1αhas further been implicated in development and carcinogenesis. Our goals are to 1) understand how the two functions of DCoH(α) are regulated, 2) determine the molecular mechanism of DCoH(α)-dependent coactivation of HNF1α-dependent transcription, and 3) ascertain how particular residue differences alter the functions of DCoH and DCoHα.
Protein Arginine Methylation
Post-translational modification of specific arginine residues of particular proteins by the additional of a methyl group is catalyzed by a family of enzymes known as the protein arginine methyl transferases (PRMTs). These PRMTs are similar to the well-studies DNA-methyltransferases in that they both use Sadenosyl methionine (SAM) as the methyl donor. The cellular response to methylation of target arginine residues within various proteins is protein-specific and has been shown to include changes in subcellular location, altered transcription rates, and the modulation of protein-protein interactions. We are interested in 1) identifying the repertoire of proteins that are methylated, 2) ascribing function to the post-translationally modified proteins and 3) understanding how the level and pattern of protein methylation changes as a function of cellular stress or disease state.
Selected Recent Publications
Chongyuan Wang, Yuwei Zhu, Tamar B Caceres, Lei Liu, Junhui Peng, Junchen Wang, Jiajing Chen,
Xuwen Chen, Zhiyong Zhang, Xiaobing Zuo, Qingguo Gong, Maikun Teng, Joan M Hevel, Jihui Wu*, and Yunyu Shi* (2014) Structural Determinants for the Strict Monomethylation Activity by Trypanosoma brucei Protein Arginine Methyltransferase 7. Accepted at Structure
Gui, S, Gathiaka, S, Li, J, Qu, J, Acevedo, O, & Hevel, JM * (2014) A remodeled protein arginine
methyltransferase 1 (PRMT1) generates symmetric dimethylarginine. J. Biol. Chem. January 29, 2014,
Gui, S, Wooderchak-Donahue, WL, Zang, T, Chen, D, Daly, MP, Zhou, ZS, & Hevel*, JM. (2012) Substrate-Induced Control of Product Formation by Protein Arginine Methyltransferase 1 (PRMT1). Biochemistry, 52 (1), pp 199–209. DOI: 10.1021/bi301283t
Gui, S., Wooderchak, W.L., Daly, M.P., Porter, P.J., Johnson, S.J., and Hevel, J.M. (2011)
Investigation of the Molecular Origins of Protein Arginine Methyltransferase I (PRMT1) Product Specificity Reveals a Role for Two Conserved Methionine Residues J. Biol. Chem. Aug 19;286(33):29118-26. doi: 10.1074/jbc.M111.224097.
Hevel, J.M. (2010) Method to Quantify Methyltransferase Activity. Patent application number: 12825548. Filed on 29 June 2010.
Suh-Lailam, B.B. & Hevel*, J.M. (2010) Rapid, Quantitative Measurement of Protein Methyltransferase Activity. Analytical Biochemistry, 398:Pages 218-224, epub 7 September 2009.
Hevel, J.M. (2009) Method to Quantify Methyltransferase Activity. Provisional patent application number: 61221453. Filed on 29 June 2009.
Suh-Lailam, B.B. & Hevel*, J.M. (2008) Efficient Cleavage of Problematic TEV-PRMT1 Constructs. Analytical Biochemistry, 387:130-2.
Wooderchak, W.L, Zhou, Z.S. & Hevel*, J.M. (2008) Assays for S-Adenosylmethionine (AdoMet/SAM)-Dependent Methyltransferses. Current Protocols in Toxicology, Supplement 38, November 2008, Unit 4.26, Wiley.
Wooderchak, W.L, Zhang, T., Zhou, Z.S., Acuna, M. Tahara, S., & Hevel*, J.M. (2008) Substrate Profiling of PRMT1 Reveals Sequences that Go Beyond the ‘RGG’ Paradigm. Biochemistry, 47:9456–9466, 2008. doi:10.1021/bi800984s
Hevel*, J.M., Pande, P., Oveson, S., Sudweeks, T., , Hansen, C. & Ayling, J.E. (2008) Determinants of Oligomerization of the Bifunctional Protein DCoHa and the Effect on its Coactivator and Enzymatic Activities. Archives of Biochemistry and Biophysics, 477:356-362. doi:10.1016/j.abb.2008.06.023
Hevel*, J.M., Olson-Buelow, L., Ganesa, B., Stevens, J.R., Hardman, J.P., & Aust, A.E. (2008) Novel Functional View of the Crocidolite-Treated A549 Human Lung Epithelial Transcriptome Reveals an Intricate Network of Pathways with Opposing Functions. BMC Genomics, 9:376. doi:10.1186/1471-2164-9-376