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Biochemistry Department - Primary Faculty

Michael E. Harris, Ph.D.

Associate Professor of Biochemistry, Case Western Reserve University
Director, Cell and Molecular Biology Training Program

Education

  • Ph.D.: University of Alabama at Birmingham, Birmingham, AL
  • Postdoc: Indiana University, Bloomington, IN

Research Interests

The overall goal of our laboratory is to understand the fundamental chemical and physical properties of RNA and proteins, and how these properties determine their roles in Biology, in particular their ability to function as catalysts. Although there have been explosive advances in understanding the structures and biological roles of RNA and protein enzymes, understanding the mechanisms by which they function at a chemical level has progressed less rapidly. This is due in part to the complexity of the problem, but also to the lack of experimental tools to reveal chemical detail. Knowledge of the chemical and physical basis of enzyme catalysis is fundamental to the design of non-biological catalysts with unique properties and the design of inhibitors as therapeutics.

The primary focus of our enzyme studies is on phosphoryl transfer, perhaps the most important enzyme catalyzed reaction in biology given its central roles in energy metabolism, storage and transfer of information contained in nucleic acids, and signal transduction. To better understand the kinds of chemical interactions that provide transition state stabilization we are analyzing the mechanisms of non-enzymatic catalyst in solution to isolate and characterize individual catalytic modes. In parallel, we are engaged in similarly detailed studies of RNA and protein enzyme mechanism to dissect the roles of individual active site residues in transition state stabilization and specificity. We are particularly interested is the role of divalent metal ions in catalysis as these are common cofactors in the active sites of both RNA and protein enzymes.

In describing RNA catalysts we are also interested in understanding the roles of metal ions play in folding the RNA polymer into its native, catalytically active structure. A key feature of our approach is the application of new biophysical and spectroscopic methods to quantify the association of metal ions with RNA and to characterize the kinds of chemical interactions that metal ions make with RNA functional groups. In doing so we are defining the chemical and biophysical linkages between RNA structure and function. Together with our enzyme studies we hope the new information we gain will provide insight into the capabilities and limitations of RNA catalysts, and help resolve the properties or macromolecules that are fundamental to biological catalysts.

Selected References

  • Wong K. Y., Gu H., Zhang S., Piccirilli J. A., Harris M. E. and York D. M.
    “Characterization of the reaction path and transition states for RNA transphosphorylation models from theory and experiment”
    Angew Chem Int Ed Engl. 51(3):647-51 (2012).

    Lee T. S., Giambaşu G., Harris M. E., and York D. M.
    “Characterization of the Structure and Dynamics of the HDV Ribozyme at Different Stages Along the Reaction Path”
    J Phys Chem Lett  2 (20):2538-43 (2011).

    Christian E. L., Anderson V. E., and Harris M. E.
    “Deconvolution of Raman spectroscopic signals for electrostatic, H-bonding, and inner-sphere interactions between ions and dimethyl phosphate in solution”
    J Inorg Biochem 105 (4): 538-47 (2011).
  • Christian E. L., Anderson V. E., Carey P. R., and Harris M. E.
    “A quantitative Raman spectroscopic signal for metal-phosphodiester interactions in solution”
    Biochemistry 49 (13): 2869-79 (2010).
  • Harris M. E. and Yandeck L. E.
    “Challenges in substrate recognition by RNase P: Facing up to the biological context”
    in Protein Reviews Volume 10: Ribonuclease P. pp 135-152. Altman S and Lui F, eds. Springer New York. ISBN 978-1-4419-1141-4 (2010).
  • Harris M. E., Dai Q., Gu H., Kellerman D. L., Piccirilli J. A., and Anderson V. E.
    “Kinetic isotope effects for RNA cleavage by 2'-O- transphosphorylation: nucleophilic activation by specific base”
    J Am Chem Soc 132 (33): 11613-21 (2010). Read article in PubMedCentral
  • Koutmou K. S., Zahler N. H., Kurz J. C., Campbell F. E., Harris M. E., and Fierke C. A.
    “Protein-precursor tRNA contact leads to sequence-specific recognition of 5' leaders by bacterial ribonuclease P”
    J Mol Biol 396 (1): 195-208 (2010). Read article in PubMedCentral
  • Sun L., Campbell F. E., Yandek L. E., and Harris M. E.
    “Binding of C5 protein to P RNA enhances the rate constant for catalysis for P RNA processing of pre-tRNAs lacking a consensus (+ 1)/C(+ 72) pair”
    J Mol Biol 395 (5): 1019-37 (2010).
  • Schroeder L. A., Gries T. J., Saecker R. M., Record M. T., Jr., Harris M. E., and DeHaseth P. L.
    “Evidence for a tyrosine-adenine stacking interaction and for a short-lived open intermediate subsequent to initial binding of Escherichia coli RNA polymerase to promoter DNA”
    J Mol Biol 385 (2): 339-49 (2009). Read article in PubMedCentral
  • Harris M. E. and Christian E. L.
    “Understanding the role of meal ions in RNA folding and function: Lessons from RNase P, a ribonucleoprotein enzyme”
    in Springer Series in Biophysics 13: Non-Protein Coding RNAs. pp183-214. Walter NG, Woodson SA and Batey RT, eds. Springer-Verlag Berlin Heidelberg ISBN 0932-2353 (2009).
  • Harris M. E.
    “Catalytic Modes of Biological Ribozymes”
    in Wiley Encyclopedia of Chemical Biology. Begley T. ed. Wiley. ISBN: 978-0-471-75477-0 .(2009).
  • Dai Q., Frederiksen J. K., Anderson V. E., Harris M. E., and Piccirilli J. A.
    “Efficient synthesis of [2'-18O]uridine and its incorporation into oligonucleotides: a new tool for mechanistic study of nucleotidyl transfer reactions by isotope effect analysis”
    J Org Chem 73 (1): 309-11 (2008).
  • Harris M. E. and Cassano A. G.
    “Experimental analyses of the chemical dynamics of ribozyme catalysis”
    Curr Opin Chem Biol 12 (6): 626-39 (2008). Read article in PubMedCentral
  • Cassano A. G., Wang B., Anderson D. R., Previs S., Harris M. E., and Anderson V. E.
    “Inaccuracies in selected ion monitoring determination of isotope ratios obviated by profile acquisition: nucleotide 18O/16O measurements”
    Anal Biochem 367 (1): 28-39 (2007). Read article in PubMedCentral
  • Sun L. and Harris M. E.
    “Evidence that binding of C5 protein to P RNA enhances ribozyme catalysis by influencing active site metal ion affinity”
    RNA 13 (9): 1505-15 (2007). Read article in PubMedCentral

 

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