Bethany A. Buck-Koehntop
Assistant Professor of Chemistry
B.S. University of Wisconsin, Stevens Point
Ph.D. University of Minnesota, Twin Cities
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Research
Our research program utilizes a multidisciplinary approach incorporating solution NMR spectroscopy with biochemistry, molecular biology and biophysical strategies to explore structure-function relationships in protein/protein and protein/nucleic acid interactions. We are particularly interested in applying these methodologies to investigate specialized transcription factors termed methyl-CpG DNA binding proteins that specifically recognize methylated DNA sequences.
In mammals DNA methylation is the primary mode of long-term transcriptional gene silencing in normal cells. Profound alterations in genomic DNA methylation patterns have also been associated with abnormal proliferation of cells preceding cancer development. These findings have prompted an interest in designing epigenetic-based cancer therapies targeting proteins involved in modification, recognition, and translation of the methylation signal. Methyl-CpG DNA binding proteins directly interpret the methylation signal leading to chromatin remodeling and gene silencing. To date, we know very little about the complex mechanisms by which these events occur.
Initial areas of interest include: 1) identifying specific DNA targets for methyl-CpG DNA binding proteins utilizing a combination of in vitro and in vivo methodologies; 2) structural investigation of these DNA interactions to ascertain differential modes of DNA recognition; and 3) structural characterization of protein/protein interactions to begin evaluating how interpretation of the methylation signal triggers chromatin remodeling. Structural evaluation of methyl-CpG DNA binding proteins with their interaction partners is critical for providing atomic-resolution detail of binding interfaces and gaining mechanistic insight into the complex roles of these proteins in cancer epigenetics. In combination with biological information, these structural studies will provide a platform for better targeted drug design..
References
1. Buck-Koehntop BA, Martinez-Yamout MA, Dyson HJ, Wright PE (2012) Kaiso uses all Three Zinc Fingers and Adjacent Sequence Motifs for High Affinity Binding to Sequence-specific and Methyl-CpG DNA Targets. FEBS Lett, 586:734-739
2. Porcelli F, Triggiani D, Buck-Koehntop BA, Masterson LR, Veglia G (2009) Pseudoenzymatic Dealkylation of Alkyltins by Biological Dithiols. J Biol Inorg Chem, 14:1219-1225
3. Lee BM, Buck-Koehntop BA, Martinez-Yamout MA, Dyson HJ, Wright PE (2007) Embryonic Neural Inducing Factor Churchill Is not a DNA-binding Zinc Finger Protein: Solution Structure Reveals a Solvent-exposed β-Sheet and Zinc Binuclear Cluster. J Mol Biol, 371:1274–1289
4. Buck-Koehntop BA, Porcelli F, Lewin JL, Cramer CJ, Veglia G (2006) Biological Chemistry of Organotin Compounds: Interactions and Dealkylation by Dithiols. J Organomet Chem, 691:1748-1755
5. Porcelli F, Buck-Koehntop BA, Thennarasu S, Ramamoorthy A, Veglia G (2006) Structures of the Dimeric and Monomeric Variants of Magainin Antimicrobial Peptides (MSI-78 and MSI-594) in Micelles and Bilayers, Determined by NMR Spectroscopy. Biochemistry, 45:5793-5799
6. Buffy JJ, Buck-Koehntop BA, Porcelli F, Traaseth NJ, Thomas DD, Veglia G (2006) Defining the Intramembrane Binding Mechanism of Sarcolipin to Calcium ATPase Using Solution NMR Spectroscopy. J Mol Biol, 358:420-429
7. Buck-Koehntop BA, Mascioni A, Buffy JJ, Veglia G (2005) Structure, Dynamics, and Membrane Topology of Stannin: A Mediator of Neuronal Cell Apoptosis Induced by Trimethyltin Chloride. J Mol Biol, 354:652-665
8. Porcelli F, Buck B, Lee DK, Hallock KJ, Ramamoorthy A, Veglia G (2004) Structure and Orientation of Pardaxin Determined by NMR Experiments in Model Membranes. J Biol Chem, 279:45815-45823
9. Buck BA, Mascioni A, Cramer CJ, Veglia G (2004) Interactions of Alkyltin Salts with Biological Dithiols: Dealkylation and Induction of a Regular β-Turn Structure. J Am Chem Soc, 126:14400-14410
10. Buck B, Mascioni A, Que L Jr, Veglia G (2003) Dealkylation of Organotin Compounds by Biological Dithiols: Toward the Chemistry of Organotin Toxicity. J Am Chem Soc, 125:13316-13317
Updated 4/11/2012
