A Unique Mechanism of Chaperone Action: Heme Regulation of Hap1 Activity Involves Separate Control of Repression and Activation

Abstract

The Hsp90 and Hsp70 molecular chaperones play important roles in the folding and proper functioning of diverse cellular proteins, including transcriptional regulators and protein kinases. In yeast, several transcriptional regulators and protein kinases are known to be substrates for Hsp90 and Hsp70 molecular chaperones. The yeast heme activator protein Hap1 promotes transcription of many genes in response to heme. It requires Hsp90 and Hsp70 molecular chaperones for its activity to be precisely regulated by heme concentration. The mechanism by which molecular chaperones promote heme regulation of Hap1 activity is distinct from the mechanism by which molecular chaperones promote steroid signaling. Hsp70 and Hsp90 molecular chaperones act separately to promote Hap1 repression in heme-deficient cells and heme activation of Hap1 in heme-sufficient cells. Likewise, distinct Hap1 elements or domains act to mediate Hap1 repression and heme activation separately. In this review, we summarize the current knowledge about the molecular mechanism governing heme regulation of Hap1 activity, and we compare this mechanism to the molecular mechanism by which Hsp90 and Hsp70 molecular chaperones promote the regulation of glucocorticoid receptor, the most extensively studied substrate of Hsp90 and Hsp70 molecular chaperones.

Heat shock proteins in toxicology: How close and how far?

“…Subsequently, Tissiers et al (1974) observed that exposure of Drosophila to heat shock resulted in the synthesis of a common set of new proteins called "heat shock proteins" (Hsps) or "stress proteins". The heat shock response has been most extensively studied in Drosophila, but a similar response has been observed in cells of a broad spectrum of eukaryotes: Saccharomyces cerevisiae (Lee and Zhang 2009), Dictyostelium (Yamaguchi et al 2005), hamsters (Talorete et al 2008), chickens (Das et al 2009), humans (Morton et al 2009) and also in prokaryotes (Sikora and Grzesiuk 2007;Vigh et al 2007).…”

Regulation of Cation Balance inSaccharomyces cerevisiae

“…This loss of heme is due, in part, to the activity of Hmx1, in part to less iron availability for insertion into heme, and in part to lower expression levels of heme biosynthetic enzymes (Lesuisse et al 2003). In addition to its role as an enzyme cofactor, heme is also a regulatory molecule that is required for the activation of the transcription factor Hap1 (Guarante 1992;Kwast et al 1998;Lee and Zhang 2009). Hap1 activates the transcription of many genes involved in respiration and aerobic growth.…”

Transcriptional Regulation inSaccharomyces cerevisiae: Transcription Factor Regulation and Function, Mechanisms of Initiation, and Roles of Activators and Coactivators

“…In the absence of heme (red star), Hap1 is held in an inactive conformation by Ssa proteins (Hsp70) and co-chaperones Ydj1 and Sro9 (orange) that bind to repression modules (RPM). Activation occurs when heme binds to heme-responsive motifs (particularly HRM7), causing association with Hsc82 (Hsp90, green crescent), apparently without dissociation of the repressive chaperones (Lee and Zhang 2009). model. Cytoplasmic Gal3 can sequester Gal80 away from the nuclear compartment in galactose-inducing conditions, suggesting that Gal80 is not bound to Gal4 at the promoter (Peng and Hopper 2000;Peng and Hopper 2002;Pilauri et al 2005).…”

“…In the absence of heme, repressive regions in the central part of Hap1 keep it in an inactive state (Hach et al 1999). In response to heme, a biosynthetic precursor of active cytochromes, repression is relieved and genes in the Hap1 regulon are activated (Lee and Zhang 2009). Heme binds in the central regulatory region of Hap1 (Zhang et al 1998;Hon et al 2000), allowing transcription activation by the C-terminal AD.…”