Research Summary

Proteins are the robots of the cell, performing various tasks to maintain cellular processes. At some time or another, proteins will specifically recognize a substrate, such as DNA, a carbohydrate, or another protein to initiate a biological event. For example, a transcription factor will bind to a specific DNA sequence to begin transcription, or a protease will recognize a particular amino acid or set of amino acids on a protein before cleaving or degrading the protein. Using x-ray crystallographic and biophysical methods, our laboratory studies protein structure and function to understand how proteins interact with substrates to control cellular processes.

The lab has two areas of interest: protein degradation and transcriptional complex assembly. Protein degradation is an important cellular mechanism that helps to regulate a plethora of physiological processes, including programmed cell death, inflammation, long-term memory, and cellular stress. Therefore, the protein degradation machines, or proteases, must degrade a wide variety of substrates under varying physiological conditions and maintain an extremely high level of selectivity. We are investigating how energy-dependent proteases specifically recognize and degrade their substrates, and how other proteins, known as adaptors, modulate substrate specificity and protease activity. In our second area of interest, we are studying transcription in Trypanosomes. Trypanosomes are unicellular parasitic protozoa that cause a wide variety of diseases in humans and domestic cattle primarily in the tropical regions of the world. However, they display remarkable evolutionary divergence from other eukaryotes and metazoans in many well-studied molecular pathways. Although transcription in Trypanosomes is not well understood, it is already clear that differences in this pathway between Trypansomes and humans could provide drug targets. To understand how transcription factors assemble to initiate transcription in these organisms and to provide a molecular foundation for drug design, our laboratory is attempting to solve x-ray structures of Trypanosome transcription factors and their complexes with DNA. For more information about the lab, please see www.wahlab.org





Selected Recent Articles


Sauer, R.T., Bolon, D.N., Burton, B.N., Burton, R.E., Flynn, J.M., Grant, R.A., Hersch, G.L., Joshi, S.A., Kenniston, J.A., Levchenko, I., Neher, S.B., Oakes, E.S., Siddiqui, S.M., Wah, D.A., and Baker, T.A. (2004). Sculpting the Proteome with AAA+ Proteases and Disassembly Machines. Cell 119, 9-18.

Wah, D.A., Levchenko, I., Rieckhof, G.E., Bolon, D.N., Baker, T.A., and Sauer, R.T. (2003). Flexible Linkers Leash the Substrate Binding Domain of SspB to a Peptide Module that Stabilizes Delivery Complexes with the AAA+ ClpXP Protease. Molecular Cell 12, 355-363.

Levchenko, I., Grant, R., Wah, D.A., Sauer, R.T., and Baker, T.A. (2003). Structure of a Delivery Protein for an AAA+ Protease in Complex with a Peptide Degradation Tag. Molecular Cell 12, 365-372.

Wah, D.A., Levchenko, I., Baker, T.A., and Sauer, R.T. (2002). Characterization of a Specificity Factor for an AAA+ ATPase: Assembly of SspB Dimers with ssrA-Tagged Proteins and the ClpX Hexamer. Chem. Biol. 9, 1237-1245.

Wah, D.A., Fernandez-Tornero, C., Sanz, L., Romero, A., and Calvete, J.J. (2002). Sperm Coating Mechanism from the 1.8 � Crystal Structure of PDC-109-Phosphorylcholine Complex. Structure 10, 505-14.

Wah, D.A., Bitinaite, J., Schildkraut, I., and Aggarwal, A.K. (1998). Structure of FokI has Implications for DNA Cleavage. Proc. Natl. Acad. Sci. USA 95, 10564-10569.

Bitinaite, J., Wah, D.A., Aggarwal, A.K., and Schildkraut, I. (1998). FokI Dimerization is Required for DNA Cleavage. Proc. Natl. Acad. Sci. USA 95, 10570-10575.

Wah, D.A., Hirsch, J.A., Dorner, L.F., Schildkraut, I., and Aggarwal, A.K. (1997). Structure of the Multimodular Endonuclease FokI Bound to DNA. Nature 388, 97-100.




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