Regulation of Hsp90 ATPase Activity by the Co-chaperone Cdc37p/p50

Siligardi, Giuliano; Panaretou, Barry; Meyer, Philippe; Singh, Sanchita; Woolfson, Derek N.; Piper, Peter W.; Pearl, Laurence H.; Prodromou, Chrisostomos

doi:10.1074/jbc.m201287200

Cited by 259 publications

(249 citation statements)

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“…In the absence of STI1, there was little stable binding of Hsp90 to the kinase, but in the same strain overexpressing CDC37, Hsp90 binding was recovered (Figure 5B). These data support the hypothesis that client loading onto Hsp90 depends on cochaperones such as Sti1 and Cdc37, which also inhibit Hsp90's ATPase (Prodromou et al, 1999;Siligardi et al, 2002;Prodromou and Pearl, 2003). It is interesting to note that yeast Cdc37 is a much less potent inhibitor of Hsp90's ATPase than is Sti1, at least in vitro (Prodromou et al, 1999;Siligardi et al, 2002).…”

Section: Discussionsupporting

confidence: 69%

“…The mechanism of Cdc37 action is not clear; Cdc37 is a molecular chaperone because it can prevent polypeptide aggregation (Kimura et al, 1997) and this function is restricted to its N-terminal domain, which is the most conserved part of the protein (Grammatikakis et al, 1999;Lee et al, 2002). Cdc37 binds directly to Hsp90 via a region of ϳ100 amino acids in the middle portion of the protein (Grammatikakis et al, 1999;Scholz et al, 2001) and partially inhibits Hsp90's ATPase (Siligardi et al, 2002). 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).…”

Section: Introductionmentioning

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: Discussionsupporting

confidence: 69%

Section: Introductionmentioning

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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“…Biochemical studies show that p50 binds to Hsp90 in a 1:1 ratio withthe interaction occuring largely at the NTD of Hsp90. The interaction also requires the charged loop and deletion of the CTD leads to a loss in affinity Siligardi et al, 2002;Zhang et al, 2004). The crystal structure of the C-terminal region of p50 (residues 148-348) bound to the NTD of Hsp90 shows a dimer for p50 but in this configuration the dimer interface is small and may arise solely from crystal contacts .…”

Section: P50 a Kinase Specific Co-chaperone Also Traps Hsp90 In An mentioning

confidence: 99%

Conformational dynamics of the molecular chaperone Hsp90

Krukenberg

Street

Lavery

et al. 2011

Quart. Rev. Biophys.

282

262

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The molecular chaperone Hsp90 is an essential eukaryotic protein that makes up 1-2% of all cytosolic proteins. Hsp90 is vital for the maturation and maintenance of a wide variety of substrate proteins largely involved in signaling and regulatory processes. Many of these substrates have also been implicated in cancer and other diseases making Hsp90 an attractive target for therapeutics. Hsp90 is a highly dynamic and flexible molecule that can adapt its conformation to the wide variety of substrate proteins with which it acts. Large conformational rearrangements are also required for the activation of these client proteins. One driving force for these rearrangements is the intrinsic ATPase activity of Hsp90, as seen with other chaperones. However, unlike other chaperones, studies have shown that the ATPase cycle of Hsp90 is not conformationally deterministic. That is, rather than dictating the conformational state, ATP binding and hydrolysis shifts the equilibrium between a pre-existing set of conformational states in an organismdependent manner. In vivo Hsp90 functions as part of larger heterocomplexes. The binding partners of Hsp90, co-chaperones, assist in the recruitment and activation of substrates, and many co-chaperones further regulate the conformational dynamics of Hsp90 by shifting the conformational equilibrium towards a particular state. Studies have also suggested alternative mechanisms for the regulation of Hsp90's conformation. In this review, we discuss the structural and biochemical studies leading to our current understanding of the conformational dynamics of Hsp90 and the role that nucleotide, co-chaperones, post-translational modification and clients play in regulating Hsp90's conformation. We also discuss the effects of current Hsp90 inhibitors on conformation and the potential for developing small molecules that inhibit Hsp90 by disrupting the conformational dynamics.

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“…While Hop/Sti1, p23, and Cdc37 impair the progression of this cycle [24,35,36], Aha1 and Cpr6 function to enhance it [35,37]. Because Hop/Sti1 and Cdc37 are both involved with the recruitment of Hsp90 client proteins, their inhibition of the ATPase cycle is thought to permit the loading of client proteins by maintaining the open clamp conformation of Hsp90 [36,38].…”

Section: Hsp90 Co-chaperonesmentioning

confidence: 99%

Hsp90—From signal transduction to cell transformation

Brown

Zhu

Schmidt

et al. 2007

Biochemical and Biophysical Research Communications

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The molecular chaperone, Hsp90, facilitates the maturation and/or activation of over 100 'client proteins' involved in signal transduction and transcriptional regulation. Largely an enigma among the families of heat shock proteins, Hsp90 is central to processes broadly ranging from cell cycle regulation to cellular transformation. Here we review the contemporary body of knowledge regarding the biochemical mechanisms of Hsp90 and update the most current paradigms defining its involvement in both normal and pathological cell physiology. KeywordsHsp90; heat shock protein; molecular chaperone; ATPase; genetic capacitor Hsp90 defines a family of molecular chaperones that are highly conserved from prokaryotes to eukaryotes [1][2][3][4][5]. Nonessential for normal growth in most bacteria, Hsp90 is abundantly expressed in higher eukaryotes where it has been shown to be necessary for viability [6,7]. It functions as a homodimer that associates with co-chaperones to catalyze the maturation and/ or activation of over 100 substrate proteins that are known to be involved in cell regulatory pathways [5]. These 'client proteins' include protein kinases, nuclear hormone receptors, transcription factors, and an array of other essential proteins [8]. While much is known regarding the ATPase-driven conformational cycling of Hsp90, the precise physical effects imparted by this chaperone that serve to activate its substrates are still poorly understood [5]. Hsp90 architectureThree highly conserved domains comprise the structure of Hsp90. These include the N-terminal domain, responsible for ATP-binding, a proteolytically resistant core domain, and the Cterminal domain that facilitates homodimerization (Fig. 1a) [9]. In eukaryotes, a more variable charged region links the N-terminal domain to the core domain. The length and composition of this linker region is highly divergent among organisms [10]. As no atomic resolution structure for full-length Hsp90 is yet available, the most thorough structural analyses for Hsp90, to date, have been based on crystallographic studies of its individual domains.A mechanistic understanding of Hsp90 was nebulous until partial sequence homology was recognized between its N-terminal domain and two types of ATP-dependent proteins. These

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Regulation of Hsp90 ATPase Activity by the Co-chaperone Cdc37p/p50

Cited by 259 publications

References 38 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

Conformational dynamics of the molecular chaperone Hsp90

Hsp90—From signal transduction to cell transformation

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