Wayne State University

Aim Higher



College of Liberal Arts & Sciences
Department of Chemistry
Faculty Page
 
Andrew Feig
Title Associate Professor
Division Biochemistry
Education B.S. Yale University 1990
Ph.D. MIT, 1995
Post-Doctoral Fellowship, 1995-1999, Univ. of Colorado, Boulder
Office Chem 455
Phone (313)577-9229
E-Mail
Group http://chem.wayne.edu/feiggroup


Our laboratory is interested in biological molecules that structurally rearrange as part of their normal activity.

Non-coding RNAs and the proteins with which they interact. Non-coding RNAs (ncRNAs) are involved in a variety of regulatory processes associated with mRNA stability and post-transcriptional gene regulation. We are using a variety of methodologies including structure mapping, CD spectroscopy, fluorescence, and microcalorimetry to probe the structural changes associated with the biology of ncRNAs. One system under study is DsrA, a ncRNA from E. coli involved in the cold shock response. Together with Hfq (Figure 1), a bacterial homolog of the Sm- and Lsm proteins, DsrA regulates RpoS translation. We have probed the different faces of Hfq and shown that they both bind RNAs but with different specificities. Hfq also interacts with a variety of proteins. We are looking at the way in which the RNAs bound to Hfq help to specify the protein components in this dynamic RNA-protein particle.

Thermodynamics of RNA Folding. RNA folding and RNA structural rearrangements are important determinants of the biological activity. We use CD, isothermal titration calorimetry (ITC) and differential scanning calorimetry (DSC) to probe these structural changes and the fundamental thermodynamics of RNA folding transitions. We have been looking extensively at heat capacity changes (ΔCP), the temperature dependence of the ΔH. We are exploring the fundamental properties of this thermodynamic parameter, such as its physical origin in RNA folding, its dependence on oligonucleotide length and sequence, its dependence on ion condensation and water interactions, and the way it responds to divalent ion binding. We have found that the ΔCP can be used, among other things, to reveal information about the residual structures in the “unfolded” state. Such structures have a major impact on isothermal folding.

Mechanistic Analysis of the Large Clostridial Cytotoxins. The laboratory is also investigating the mechanistic enzymology and biophysics of toxins A and B from Clostridium difficile, a common enteric bacterium. Infection with this organism is the primary cause of antibiotic-associated diarrhea (a condition that afflicts >3 million patients annually). Toxins A and B catalyze mono-glucosylation of the RhoA sub-family of small G-proteins, inducing apoptosis in the afflicted cells. We have cloned and expressed both the 66kD glucosyltransferase domain as well as the intact 300 kD holotoxin. We are using these materials to explore structural transitions required for translocation across cellular membranes during pathogenesis and substrate recognition.


Figure 1. Hfq hexamerizes to form a very stable toroidal structure. The top and bottom faces both bind RNAs but the sites have different specificities and functions.



REPRESENTATIVE PUBLICATIONS


C. difficile Toxin:

Swett, R., Cisneros, G. A., Feig, A. L. (2012) Conformational Analysis of Clostridium difficile Toxin B and its Implications for Substrate Recognition. PLOS One. 7(7): e41518. doi:10.1371/journal.pone.0041518

Kern, S. M. and Feig, A. L. (2011) Adaptation of Clostridium difficile toxin A for use as a protein translocation system. Biochem. Biophys. Res. Commun.405(4) 570-574. doi:10.1016/j.bbrc.2011.01.070.

Abdeen, S. J., Swett, R. J., and Feig, A. L. (2010) Peptide inhibitors targeting Clostridium difficile toxins A and B, ACS Chem Biol 5, 1097-1103.

RNA Biochemistry and Biophysics:

Salim, N.N., Faner, M.A., Philip, J., and Feig, A. L. (2012) Requirement of Upstream Hfq Binding (ARN)x Elements in glmS and the Hfq C-Terminal Region for GlmS Up-regulation by sRNAs GlmZ and GlmY. Nucl. Acids Res. 40, 8021-32. doi:10.1093/nar/gks392

Salim, N. Lamichhane, Zhao, R. Banerjee, T. R. Rueda, D and Feig, AL. (2012) Thermodynamic and Kinetic

Analysis of an RNA Kissing Interaction and its Resolution into an Extended Duplex. Biophys. J.102, 1097-1107. doi:10.1016/j.bpj.2011.12.052

Salim NN, Feig AL. (2010) An upstream Hfq binding site in the fhlA mRNA leader region facilitates the OxyS-fhlA interaction. PLoS One. 2010 Sep 28;5(9). pii: e13028. PMID: 20927406

Mikulecky, PJ and Feig, AL. (2006) Heat Capacity Changes Associated with Nucleic Acid Folding. Biopolymers, 82, 38-58.

DEPARTMENT OF CHEMISTRY ©
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