A Cyclophilin Function in Hsp90-Dependent Signal Transduction

Duina, Andrea A.; Chang, Hui; Marsh, James A.; Lindquist, Susan; Gaber, Richard F.

doi:10.1126/science.274.5293.1713

Cited by 221 publications

(190 citation statements)

References 22 publications

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“…Furthermore, comparison of the results presented here with those previously reported using heterologous clients reveals some common trends. Deletion of CPR6 or SBA1, for example, results in a only a slight defect in v-Src or nuclear receptor signaling, whereas deletion of CPR7 or YDJ1 resulted in strong signaling defects (Kimura et al, 1995;Dey et al, 1996;Duina et al, 1996;Warth et al, 1997;Fang et al, 1998). By correlation, cochaperones that are essential for viability are also likely to play essential roles in the folding pathway; examples here are Cdc37 and Cns1.…”

Section: Discussionmentioning

confidence: 99%

“…Levels of FIG1 and HHF1 mRNA were determined by quantitative real-time rtPCR relative to ARP5, whose mRNA levels do not change upon pheromone treatment (Roberts et al, 2000; our unpublished results). The cochaperones chosen for study have all been characterized previously as Hsp90 binding proteins, and include Cpr6, Cpr7, Hch1, Sba1, Sse1, and Sti1 (Duina et al, 1996;Chang et al, 1997;Bohen, 1998;Fang et al, 1998;Liu et al, 1999;Panaretou et al, 2002;Lotz et al, 2003). Ydj1, a cochaperone of Hsp70 was also included because it affects the activity of Hsp90 clients (Bohen et al, 1995).…”

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confidence: 99%

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Sti1 and Cdc37 Can Stabilize Hsp90 in Chaperone Complexes with a Protein Kinase

Lee

Shabbir

Cardozo

et al. 2004

MBoC

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Hsp90 functions in association with several cochaperones for folding of protein kinases and transcription factors, although the relative contribution of each to the overall reaction is unknown. We assayed the role of nine different cochaperones in the activation of Ste11, a Saccharomyces cerevisiae mitogen-activated protein kinase kinase kinase. Studies on signaling via this protein kinase pathway was measured by ␣-factor-stimulated induction of FIG1 or lacZ, and repression of HHF1. Several cochaperone mutants tested had reduced FIG1 induction or HHF1 repression, although to differing extents. The greatest defects were in cpr7⌬, sse1⌬, and ydj1⌬ mutants. Assays of Ste11 kinase activity revealed a pattern of defects in the cochaperone mutant strains that were similar to the gene expression studies. Overexpression of CDC37, a chaperone required for protein kinase folding, suppressed defects the sti1⌬ mutant back to wild-type levels. CDC37 overexpression also restored stable Hsp90 binding to the Ste11 protein kinase domain in the sti1⌬ mutant strain. These data suggest that Cdc37 and Sti1 have functional overlap in stabilizing Hsp90:client complexes. Finally, we show that Cns1 functions in MAP kinase signaling in association with Cpr7. INTRODUCTIONAmong several major classes of molecular chaperone that have been characterized, Hsp90 appears to function primarily in folding of signal transducing proteins such as transcription factors and protein kinases (Caplan, 1999;Prodromou and Pearl, 2003). Hsp90 does not act alone in this capacity, but in association with several cochaperones that may also have chaperone function as defined by their ability to prevent polypeptide aggregation in vitro.The current understanding of how Hsp90 cochaperones function derived from in vitro studies on progesterone receptors (PR) and glucocorticoid receptors (GR; Toft, 1997, 2003). The results of these studies showed that Hsp70 and Hsp40 first interact with the receptor ligandbinding domain. Hsp90 is recruited into this complex by the cochaperone called Hop, which interacts with both Hsp90 and Hsp70. Subsequently, Hsp70 and Hop are displaced by other cochaperones, such as one of many immunophilins and p23. Folding occurs in association with ATP hydrolysis by Hsp90, which is stimulated by another cochaperone called Aha1 (and its paralog Hch1; Panaretou et al., 2002;Lotz et al., 2003). It is unclear whether folding occurs while the receptor is in association with Hsp90 or after its release. Whether the cochaperones are required for this reaction is not clear, because purified Hsp70 and Hsp90 can together facilitate folding of GR in vitro, whereas cochaperones such as Hop stimulate the reaction (Morishima et al., 2000;Rajapandi et al., 2000). Furthermore, deletion of yeast Hop (STI1), or p23 (SBA1) does not result in a slow growth phenotype except under stress conditions (Nicolet and Craig, 1989;Chang et al., 1997;Bohen, 1998;Fang et al., 1998).Another question is whether the scheme described above for nuclear receptors reflects a set of ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Sti1 and Cdc37 Can Stabilize Hsp90 in Chaperone Complexes with a Protein Kinase

Lee

Shabbir

Cardozo

et al. 2004

MBoC

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“…Previous studies have shown that the deletion of Cpr6 has no effect on the viability of yeast cells (55,29,31). In contrast, the deletion of Cpr7 caused a growth defect (28,45). Additionally, Cpr7-depleted cells are more sensitive to geldanamycin, a specific Hsp90 inhibitor, and are defective in restoring the full glucocorticoid receptor activity (30).…”

Section: Catalytic Activity Of the Large Immunophilins In The Accelermentioning

confidence: 98%

Cpr6 and Cpr7, Two Closely Related Hsp90-associated Immunophilins from Saccharomyces cerevisiae, Differ in Their Functional Properties

Mayr

Richter

Lilie

et al. 2000

Journal of Biological Chemistry

106

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Hsp90 is an abundant cytosolic molecular chaperone. It controls the folding of target proteins including steroid hormone receptors and kinases in complex with several partner proteins. Prominent members of this protein family are large peptidyl prolyl cis/trans isomerases (PPIases), which catalyze the cis/trans isomerization of prolyl peptide bonds in proteins and possess chaperone activity. In Saccharomyces cerevisiae, two closely related large Hsp90-associated PPIases, Cpr6 and Cpr7, exist. We show here that these homologous proteins bind with comparable affinity to Hsp90 but exhibit significant structural and functional differences. Cpr6 is more stable than Cpr7 against thermal denaturation and displays an up to 100-fold higher PPIase activity. In contrast, the chaperone activity of Cpr6 is much lower than that of Cpr7. Based on these results we suggest that the two immunophilins perform overlapping but not identical tasks in the Hsp90 chaperone cycle. PPIases1 are enzymes that are able to catalyze the cis-trans isomerization of Xaa-Pro peptide bonds in short synthetic peptides as well as in proteins (1). The isomerization of these bonds is a slow process (2) and often a rate-determining step in protein folding (3-6). PPIases have been found in all organisms and subcellular compartments studied so far (1,7,8). Until now three unrelated families of PPIases could be identified: parvulins, cyclophilins, and FKBPs (1,5,9). Because of their inhibition by the immunosuppressive drugs cyclosporin A (CsA) or FK506/rapamycin, the cyclophilins and FKBPs are also termed immunophilins (10 -13). Several large immunophilins with a molecular mass of about 40 -54 kDa are components of the Hsp90 chaperone complex. In higher eukaryotes, FKBP51, FKBP52, and Cyp40 act together with Hsp90; in yeast these are Cpr6 and Cpr7, two cyclophilins. The Hsp90 complex seems to regulate the conformation of its target proteins. These substrates include steroid hormone receptors. Here, the Hsp90 chaperone cycle is well established (reviewed in Refs. 14 -16).In the case of the progesterone receptor, the receptor is bound to Hsp70 in an early complex (15,17). Then an intermediate complex is formed in which Hsp90, Hsp70, Hip, Hop, and perhaps Hsp40 participate. The last step of this activation cycle is a complex, consisting of the progesterone receptor, Hsp90, p23, and one of the large immunophilins. The specific function of the immunophilins in the chaperone cycle is far from clear. However, it is well established that progesterone receptor has to be bound in this complex to allow binding of the hormone, dimerization, and subsequently, interaction with DNA. In the absence of hormone, the receptor is released from the complex, and the cycle starts again. The large immunophilins interact with Hsp90 via tetratricopeptide repeats (18 -21). The partner site for the tetratricopeptide-repeat motifs is located in a 12-kDa carboxyl-terminal domain of Hsp90 (22, 23). The tetratricopeptide-repeat proteins compete with each other for this binding site (18,1...

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“…However, regions of high homology to Sti1 can only be found in the TPR domain of Cns1. In contrast to other co-chaperones containing a TPR domain, Cns1 is essential in yeast (4,23,(25)(26)(27)(28). Overexpression of Sti1, or of other TPR-containing proteins cannot compensate for the lethality of ⌬Cns1 (23,29).…”

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confidence: 99%

Cns1 Is an Activator of the Ssa1 ATPase Activity

Hainzl¹,

Wegele²,

Richter

et al. 2004

Journal of Biological Chemistry

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Hsp90 is a key mediator in the folding process of a growing number of client proteins. The molecular chaperone cooperates with many co-chaperones and partner proteins to fulfill its task. In Saccharomyces cerevisiae, several co-chaperones of Hsp90 interact with Hsp90 via a tetratricopeptide repeat (TPR) domain. Here we show that one of these proteins, Cns1, binds both to Hsp90 and to the yeast Hsp70 protein Ssa1 with comparable affinities. This is reminiscent of Sti1, another TPR-containing co-chaperone. Unlike Sti1, Cns1 exhibits no influence on the ATPase of Hsp90. However, it activates the ATPase of Ssa1 up to 30-fold by accelerating the ratelimiting ATP hydrolysis step. This stimulating effect is mediated by the N-terminal TPR-containing part of Cns1, whereas the C-terminal part showed no effect. Competition experiments allow the conclusion that Hsp90 and Ssa1 compete for binding to the single TPR domain of Cns1. Taken together, Cns1 is a potent cochaperone of Ssa1. Our findings highlight the importance of the regulation of Hsp70 function in the context of the Hsp90 chaperone cycle.

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A Cyclophilin Function in Hsp90-Dependent Signal Transduction

Cited by 221 publications

References 22 publications

Sti1 and Cdc37 Can Stabilize Hsp90 in Chaperone Complexes with a Protein Kinase

Sti1 and Cdc37 Can Stabilize Hsp90 in Chaperone Complexes with a Protein Kinase

Cpr6 and Cpr7, Two Closely Related Hsp90-associated Immunophilins from Saccharomyces cerevisiae, Differ in Their Functional Properties

Cns1 Is an Activator of the Ssa1 ATPase Activity

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