Activation of the ATPase Activity of Hsp90 by the Stress-Regulated Cochaperone Aha1

Panaretou, Barry; Siligardi, Giuliano; Meyer, Philippe; Maloney, Alison; Sullivan, Janis K.; Singh, Sanchita; Millson, Stefan H.; Clarke, Paul A.; Naaby-Hansen, Søren; Stein, Robert; Cramer, Rainer; Mollapour, Mehdi; Workman, Paul; Piper, Peter W.; Pearl, Laurence H.; Prodromou, Chrisostomos

doi:10.1016/s1097-2765(02)00785-2

Cited by 483 publications

(506 citation statements)

References 36 publications

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“…Unlike the other co-chaperones discussed, Aha1 stimulates the ATPase activity of Hsp90 (Lotz et al, 2003;Meyer et al, 2004;Panaretou et al, 2002). Aha1 binds mainly to the MD domain of Hsp90 and this interaction is mediated by the N-terminal portion of Aha1 (NAha1) (Lotz et al, 2003;Meyer et al, 2004;Siligardi et al, 2004).…”

Section: Aha1 Activates the Atpase Of Hsp90mentioning

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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Section: Aha1 Activates the Atpase Of Hsp90mentioning

confidence: 99%

Conformational dynamics of the molecular chaperone Hsp90

Krukenberg

Street

Lavery

et al. 2011

Quart. Rev. Biophys.

282

262

View full text Add to dashboard Cite

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“…Cochaperones such as HOP and p23 inhibit Hsp90's ATPase activity and are likely to be involved in client loading or the formation of a Hsp90-client substrate complex (McLaughlin et al, 2006;Schmid et al, 2012;Southworth and Agard, 2011;Young and Hartl, 2000). The co-chaperone AHA1 (Activator of Hsp90 ATPase homologue 1) stimulates the Hsp90 conformational cycle by enhancing the ATPase activity and permitting the substrate release for the next maturation step (Meyer et al, 2004;Panaretou et al, 2002). Some co-chaperones like HOP and CHIP play an essential role in facilitating the cooperative and successive action of Hsp40, Hsp70 and Hsp90 on client proteins to promote either folding or degradation.…”

Section: Ii41122 the Hsp90 Chaperone Systemmentioning

confidence: 99%

Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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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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Activation of the ATPase Activity of Hsp90 by the Stress-Regulated Cochaperone Aha1

Cited by 483 publications

References 36 publications

Conformational dynamics of the molecular chaperone Hsp90

Conformational dynamics of the molecular chaperone Hsp90

Firefly luciferase mutants as sensors of proteome stress

Hsp90—From signal transduction to cell transformation

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