Research

The goal of my research is to determine the physical basis of interactions between the Hsp90 (90-kilodalton heat shock protein) chaperone and its substrate (“client”) proteins.  Hsp90 is essential in all eukaryotes. It is critically required for the maintenance and regulation of proteins involved in the cell cycle, signal transduction, cell fate, and transcription. Hsp90 substrate interactions are important in disease prevention. For example, pharmacological suppression of Hsp90 can have potent antiviral effects, as well as inhibiting the maturation of a wide variety of kinase substrates, many of which are over-expressed in malignant cells. Thus, Hsp90 inhibitors are currently undergoing clinical trials as treatments for a variety of cancers.

Despite the obvious importance of Hsp90, the molecular basis of its function is poorly understood. Only recently have three-dimensional structures of the full-length Hsp90 been determined (apo, ADP; Agard lab, ATP Pearl lab) and a reaction cycle been proposed. However, remarkably little is known about the molecular basis for substrate binding and subsequent activation. Currently, I am investigating interactions between Hsp90 and citrate synthase, as it has been shown that Hsp90 can inhibit the thermal aggregation of this protein.

Publications

Street TO, Courtemanche N, Barrick D., Protein folding and stability using denaturants. Methods Cell Biol. 2008;84:295-325.

Street TO, Fitzkee NC, Perskie LL, Rose GD., Physical-chemical determinants of turn conformations in globular proteins. Protein Sci. 2007 Aug;16(8):1720-7.

Street TO, Bradley CM, Barrick D., Predicting coupling limits from an experimentally determined energy landscape. Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):4907-12. Epub 2007 Mar 14.

Street TO, Bolen DW, Rose GD. A molecular mechanism for osmolyte-induced protein stability. Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):13997-4002. Epub 2006 Sep 12. Erratum in: Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):17064.

Street TO, Rose GD, Barrick D., The role of introns in repeat protein gene formation. J Mol Biol. 2006 Jul 7;360(2):258-66. Epub 2006 May 24.

Street TO, Bradley CM, Barrick D., An improved experimental system for determining small folding entropy changes resulting from proline to alanine substitutions. Protein Sci. 2005 Sep;14(9):2429-35.

Fitzkee NC, Fleming PJ, Gong H, Panasik N Jr, Street TO, Rose GD., Are proteins made from a limited parts list? Trends Biochem Sci. 2005 Feb;30(2):73-80.