The Hsp90 Co-Chaperones Cdc37 and Sti1 Interact Physically and Genetically

Abbas-Terki, Toufik; Briand, Pierre-André; Donzé, Olivier; Picard, Didier

doi:10.1515/bc.2002.152

Cited by 46 publications

(40 citation statements)

References 52 publications

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“…We still lack some technical tools to further dissect the details of how Hop and Cdc37 function during kinase folding. However, our data suggest a cooperative model for these cochaperones, consistent with other biochemical evidence of Sti1-Cdc37 complexes in yeast or reticulocyte lysates (Hartson et al 2000;Abbas-Terki et al 2002).…”

Section: Discussionsupporting

confidence: 91%

Functioning of the Hsp90 machine in chaperoning checkpoint kinase 1 (Chk1) and the progesterone receptor (PR)

Felts¹,

Karnitz²,

Toft³

2005

Cell Stress Chaper

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Hsp90 is an abundant and highly conserved chaperone that functions at later stages of protein folding to maintain and regulate the activity of client proteins. Using a recently described in vitro system to fold a functional model kinase Chk1, we performed a side-by-side comparison of the Hsp90-dependent chaperoning of Chk1 to that of the progesterone receptor (PR) and show that these distinct types of clients have different chaperoning requirements. The less stable PR required more total chaperone protein(s) and p23, whereas Chk1 folding was critically dependent on Cdc37. When the 2 clients were reconstituted under identical conditions, each client folding was dose dependent for Hsp90 protein levels and was inhibited by geldanamycin. Using this tractable system, we found that Chk1 kinase folding was more effective if we used a type II Hsp40 cochaperone, whereas PR is chaperoned equally well with a type I or type II Hsp40. Additional dissection of Chk1-chaperone complexes and the resulting kinase activity suggests that kinase folding, like that previously shown for PR, is a dynamic, multistep process. Importantly, the cochaperones Hop and Cdc37 cooperate as the kinase transitions from immature Hsp70-to mature Hsp90-predominant complexes.

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Section: Discussionsupporting

confidence: 91%

Functioning of the Hsp90 machine in chaperoning checkpoint kinase 1 (Chk1) and the progesterone receptor (PR)

Felts¹,

Karnitz²,

Toft³

2005

Cell Stress Chaper

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“…This is supported by our findings that deletion of STI1 prevents stable complex formation between the client and Hsp90. Because Cdc37 can also interact with the client, Hsp90 and Sti1 (Abbas-Terki et al, 2002), it is likely that multiple interactions lead to stable formation of the subsequent chaperone:client complexes. On the other hand, it still remains unclear how such stability contributes to the overall efficiency of the folding reaction.…”

Section: Discussionmentioning

confidence: 99%

“…This indicates that Cpr7 has a separate function from Cdc37, although both chaperones are clearly part of the same Hsp90 machinery and indeed have been shown to interact with each other (Abbas-Terki et al, 2002). Previous studies established that the growth phenotype of cpr7⌬ could be suppressed by CNS1 overexpression, as could a defect in GR activation (Dolinski et al, 1998;Marsh et al, 1998).…”

Section: Suppression Of Cpr7⌬ By Cns1 For Map Kinase Signalingmentioning

confidence: 96%

“…The C-terminal 118 amino acids (of 506) are completely dispensable for its function in yeast (Lee et al, 2002 with their coexistence on the same Hsp90 molecule (Silverstein et al, 1998;Hartson et al, 2000). Furthermore, yeast Cdc37 can interact with both Sti1/Hop and Cpr7 (an immunophilin) independently of Hsp90 (Abbas-Terki et al, 2002). Thus it is possible that Cdc37 enters the chaperone-dependent folding pathway via interaction with other cochaperones, although this remains to be tested.…”

mentioning

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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“…Some of these accessory proteins might not only bind to the Hsp90 chaperone core but associate with each other directly. For example, interactions of p50/Cdc37 with the TPR cofactors Hop and cyclophilin Cpr7 were reported in cell lysates [19] and yeast [27], although this finding has not been verified in a pure biochemical system. Moreover, the identification of the novel Hsp90 cofactor Aha1, which binds to the middle domain of the chaperone [11,23], motivated us to analyse its relationship with other cofactors of the molecular chaperone.…”

Section: Direct Interactions Between Hsp90 Cofactorsmentioning

confidence: 97%

Aha1 competes with Hop, p50 and p23 for binding to the molecular chaperone Hsp90 and contributes to kinase and hormone receptor activation

Harst

Lin

Obermann

2005

Biochemical Journal

119

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The ATP-dependent molecular chaperone Hsp90 (heat-shock protein 90) is essential for the maturation of hormone receptors and protein kinases. During the process of client protein activation, Hsp90 co-operates with cofactors/co-chaperones of unique sequence, e.g. Aha1 (activator of Hsp90 ATPase 1), p23 or p50, and with cofactors containing TPR (tetratricopeptide repeat) domains, e.g. Hop, immunophilins or cyclophilins. Although the binding sites for these different types of cofactors are distributed along the three domains of Hsp90, sterical overlap and competition for binding sites restrict the combinations of cofactors that can bind to Hsp90 at the same time. The recently discovered cofactor Aha1 associates with the middle domain of Hsp90, but its relationship to other cofactors of the molecular chaperone is poorly understood. Therefore we analysed whether complexes of Aha1, p23, p50, Hop and a cyclophilin with Hsp90 are disrupted by the other four cofactors by gel permeation chromatography using purified proteins. It turned out that Aha1 competes with the early cofactors Hop and p50, but can bind to Hsp90 in the presence of cyclophilins, suggesting that Aha1 acts as a late cofactor of Hsp90. In contrast with p50, which can bind to Hop, Aha1 does not interact directly with any of the other four cofactors. In vivo studies in yeast and in mammalian cells revealed that Aha1 is not specific for kinase activation, but also contributes to maturation of hormone receptors, proposing a general role for this cofactor in the activation of Hsp90-dependent client proteins.

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The Hsp90 Co-Chaperones Cdc37 and Sti1 Interact Physically and Genetically

Cited by 46 publications

References 52 publications

Functioning of the Hsp90 machine in chaperoning checkpoint kinase 1 (Chk1) and the progesterone receptor (PR)

Functioning of the Hsp90 machine in chaperoning checkpoint kinase 1 (Chk1) and the progesterone receptor (PR)

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

Aha1 competes with Hop, p50 and p23 for binding to the molecular chaperone Hsp90 and contributes to kinase and hormone receptor activation

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