Structural Analysis of E. coli hsp90 Reveals Dramatic Nucleotide-Dependent Conformational Rearrangements

Shiau, Andrew K.; Harris, S.F.; Southworth, Daniel R.; Agard, David A.

doi:10.1016/j.cell.2006.09.027

Cited by 411 publications

(601 citation statements)

References 37 publications

(70 reference statements)

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“…This is in contrast to other GHKL family members such as MutL where the lid becomes more ordered in the presence of nucleotide (Ban et al, 1999). Two additional lid positions are seen in different crystals of ADP-bound HtpG ( Figure 4D) (Shiau et al, 2006).…”

Section: Local Structural Changes In the Ntd Due To Nucleotide Bindingmentioning

confidence: 69%

“…The full length structure of apo HtpG supports this idea. In this structure the lid adopts a unique position orthogonal to the NTD β-sheet as opposed to parallel to the β-sheet as seen in other structures (Figure 4) (Shiau et al, 2006). This lid conformation precludes ATP binding by positioning residue F123 where the base and sugar of the nucleotide would be positioned, blocking access to the binding pocket.…”

Section: Local Structural Changes In the Ntd Due To Nucleotide Bindingmentioning

confidence: 79%

“…This charged region is also present in the bacterial protein HtpG, but it is significantly shorter in length. This region was originally believed to be a flexible tether between the two domains, but crystal structures have shown structured elements on either side of this charged region that are part of the NTD leaving only a few amino acids as the linker between the NTD and MD Huai et al, 2005;Shiau et al, 2006;Soldano et al, 2003). Though the charged region is dispensible in yeast, it has been implicated in the binding of substrates.…”

Section: Architecture Of Hsp90mentioning

confidence: 99%

“…The ability to adapt structurally may be one mechanism by which Hsp90 is able to recognize such a wide variety of client proteins. A crystal structure of the bacterial Hsp90 shows the apo (nucleotide-free) protein in an open V-like conformation with only the CTDs dimerized (Figure 3) (Shiau et al, 2006). In this structure hydrophobic surfaces are presented along the inner cleft of the dimer suggesting a means of substrate recognition (Figure 3,purple,(326)(327)(328)(329)(330)(331)(332)(333)(334)(335)(336)(337)(338)(339)(340)(341)(342)(368)(369)(370)(371)(372)(373)(374)(375)(376)(377)(378)(379)(380)(381)(382)(383)(384)Hsp82 numbering).…”

Section: Global Conformational Changes In the Full-length Proteinmentioning

confidence: 99%

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Conformational dynamics of the molecular chaperone Hsp90

Krukenberg

Street

Lavery

et al. 2011

Quart. Rev. Biophys.

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271

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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: Local Structural Changes In the Ntd Due To Nucleotide Bindingmentioning

confidence: 69%

Section: Local Structural Changes In the Ntd Due To Nucleotide Bindingmentioning

confidence: 79%

Section: Architecture Of Hsp90mentioning

confidence: 99%

Section: Global Conformational Changes In the Full-length Proteinmentioning

confidence: 99%

See 2 more Smart Citations

Conformational dynamics of the molecular chaperone Hsp90

Krukenberg

Street

Lavery

et al. 2011

Quart. Rev. Biophys.

Self Cite

271

262

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show abstract

“…The advent of the C-terminal crystal structure provided further evidence for the antiparallel dimeric architecture of Hsp90 that had been previously predicted by electron microscopy [20][21][22]. C-terminal truncations of Hsp90 abolish its ability to hydrolyze ATP, indicating that its dimeric nature is essential for its activity [13].…”

mentioning

confidence: 68%

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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The roles of molecular chaperones in regulating cell metabolism

Binder

Pedley

2023

FEBS Letters

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Fluctuations in nutrient and biomass availability, often as a result of disease, impart metabolic challenges that must be overcome in order to sustain cell survival and promote proliferation. Cells adapt to these environmental changes and stresses by adjusting their metabolic networks through a series of regulatory mechanisms. Our understanding of these rewiring events has largely been focused on those genetic transformations that alter protein expression and the biochemical mechanisms that change protein behavior, such as post‐translational modifications and metabolite‐based allosteric modulators. Mounting evidence suggests that a class of proteome surveillance proteins called molecular chaperones also can influence metabolic processes. Here, we summarize several ways the Hsp90 and Hsp70 chaperone families act on human metabolic enzymes and their supramolecular assemblies to change enzymatic activities and metabolite flux. We further highlight how these chaperones can assist in the translocation and degradation of metabolic enzymes. Collectively, these studies provide a new view for how metabolic processes are regulated to meet cellular demand and inspire new avenues for therapeutic intervention.

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Structural Analysis of E. coli hsp90 Reveals Dramatic Nucleotide-Dependent Conformational Rearrangements

Cited by 411 publications

References 37 publications

Conformational dynamics of the molecular chaperone Hsp90

Conformational dynamics of the molecular chaperone Hsp90

Hsp90—From signal transduction to cell transformation

The roles of molecular chaperones in regulating cell metabolism

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