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RESEARCH INTERESTS: Reproductive Steroid Hormone Action
RESEARCH SUMMARY: My laboratory is interested in the roles of molecular chaperones in regulating signal transduction pathways. In particular, we study the function of the cytosolic chaperone Hsp90, which interacts with a diverse subset of client proteins, ranging from steroid hormone receptors to protein kinases. Hsp90, along with a number of co-chaperone proteins, interacts with client proteins in an ordered, ATP-dependent pathway that is conserved from yeast to plants to humans. We use a combined genetic and biochemical approach in Saccharomyces cerevisiae to dissect the individual roles of the co-chaperones in this folding pathway. Current work focuses on characterizing the direct interaction between the Hsp40 Ydj1 and heterologous steroid receptors. Ydj1 binds steroid receptors prior to Hsp90 and the other co-chaperones. In the absence of functional Ydj1, receptor becomes constitutively active, suggesting that Ydj1 interaction is required to bring steroid receptors under hormonal control. Additional studies will focus on understanding the diverse roles of the Hsp90 pathway in the cell cycle. Yeast containing mutations in the Hsp90 pathway exhibit multiple defects in pheromone signaling, such as decreased activity of the Ste11 kinase, which interacts with Hsp90, and decreased processing of both a-factor and alpha factor. By using both heterologous and native client proteins we hope to better understand how the Hsp90 molecular chaperone affects multiple cellular signaling pathways. REPRESENTATIVE PUBLICATIONS: Flom G, Weekes J, Williams J, and Johnson JL. 2006 Effect of mutation of the TPR and DP2 domains of Sti1 on Hsp90 signaling and interaction in Saccharomyces cerevisiae. Genetics. 172(1):41-51.
Hon T, Lee HC, Hach A, Johnson JL, Craig EA, Erdjument-Bromage H, Tempst P, and Zhang L. The Hsp70-Ydj1 molecular chaperone represses the activity of the heme activator protein Hap1 in the absence of heme. Molec. Cell Biol. 21(23):7923-32. (2001) Johnson JL and Craig EA. An essential role for substrate-binding by Hsp40s in Saccharomyces cerevisiae. J. Cell Biol. 152(4):851-856. (2001) Johnson JL and Craig EA. Identifying functional interactions with Molecular Chaperones. In Methods in Enzymology: Guide to Yeast Genetics and Molecular Cell Biology. C. Guthrie and G.R.Fink, ed. (Academic Press, San Diego). In press. Johnson JL and Craig EA. A role for the Hsp40 Ydj1 in repression of basal steroid receptor activity in yeast. Molec. Cell. Biol. 20:3027-3036. (2000). Johnson JL, and Craig EA. Protein folding in vivo: Unraveling complex pathways. Cell 90: 201-204. (1997). (minireview) Johnson, JL. Three chapters, P23, P60 and Sti1 in Guidebook
to Molecular Chaperones and Protein Folding Factors. M.-J. Gething,
ed. (Oxford: Sambrook & Tooze at Oxford University Press).
p.457-459 (1997). Ziegelhoffer T, Johnson JL, and Craig EA. Protein folding: Chaperones get Hip. Current Biology 6:272-275, 1996. (minireview) Hutchinson KA, Stancato LF, Owens-Grillo JK, Johnson JL, Krishna P, Toft DO, and Pratt WB. The 23 kDa acidic protein in reticulocyte lysate is the weakly bound component of the hsp foldosome that is required for assembly of the glucocorticoid receptor into a functional heterocomplex with hsp90. J. Biological Chem. 270:18841-18847, 1995 Johnson J, Corbisier R, Stensgard B, and Toft DO. The involvement of p23, hsp90, and immunophilins in the assembly of progesterone receptor complexes. J. Steroid Biochem. Molec. Biol. 56:31-37, 1996. Johnson JL, and Toft DO. Binding of p23 and hsp90 during assembly with the progesterone receptor. Molec. Endocrinology 9:670-678, 1995. Johnson JL, and Toft DO. A novel chaperone complex for steroid receptors involving heat shock proteins, immunophilins, and p23. J. Biological Chem. 269:24989-24993, 1994. Johnson JL, Beito TG, Krco CJ, and Toft DO. Characterization of a novel 23 kDa protein of unactivated progesterone receptor complexes. Molec. Cell. Biol. 14:1956-1963, 1994. Smith DF, Sullivan WP, Johnson JL, and Toft DO. In vitro assembly
of the avian progesterone receptor. In: Steroid receptors in
health and disease. V. K. Moudgil, ed. Birkhauser Press, Berlin.
p. 247-260, 1993.
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