Skip to main content
×
Home
    • Aa
    • Aa
  • Get access
    Check if you have access via personal or institutional login
  • Cited by 64
  • Cited by
    This article has been cited by the following publications. This list is generated based on data provided by CrossRef.

    Borges, Júlio C. Seraphim, Thiago V. Dores-Silva, Paulo R. and Barbosa, Leandro R. S. 2016. A review of multi-domain and flexible molecular chaperones studies by small-angle X-ray scattering. Biophysical Reviews, Vol. 8, Issue. 2, p. 107.


    Cele, Favourite N. Kumalo, Hezekiel and Soliman, Mahmoud E. S. 2016. Mechanism of Inhibition of Hsp90 Dimerization by Gyrase B Inhibitor Coumermycin A1 (C–A1) Revealed by Molecular Dynamics Simulations and Thermodynamic Calculations. Cell Biochemistry and Biophysics,


    Chavez, Juan D. Schweppe, Devin K. Eng, Jimmy K. and Bruce, James E. 2016. In Vivo Conformational Dynamics of Hsp90 and Its Interactors. Cell Chemical Biology, Vol. 23, Issue. 6, p. 716.


    Ghosh, Arnab and Stuehr, Dennis J. 2016. Regulation of sGCviahsp90, Cellular Heme, sGC Agonists, and NO: New Pathways and Clinical Perspectives. Antioxidants & Redox Signaling,


    Hongmao, Sun 2016. A Practical Guide to Rational Drug Design.


    Kokh, Daria B. Czodrowski, Paul Rippmann, Friedrich and Wade, Rebecca C. 2016. Perturbation Approaches for Exploring Protein Binding Site Flexibility to Predict Transient Binding Pockets. Journal of Chemical Theory and Computation, Vol. 12, Issue. 8, p. 4100.


    Lo, Hui-Fen Chen, Bo-En Lin, Min-Guan Chi, Meng-Chun Wang, Tzu-Fan and Lin, Long-Liu 2016. Gene expression and molecular characterization of a chaperone protein HtpG from Bacillus licheniformis. International Journal of Biological Macromolecules, Vol. 85, p. 179.


    Pellati, Federica and Rastelli, Giulio 2016. Novel and less explored chemotypes of natural origin for the inhibition of Hsp90. Med. Chem. Commun.,


    Schulze, Andrea Beliu, Gerti Helmerich, Dominic A Schubert, Jonathan Pearl, Laurence H Prodromou, Chrisostomos and Neuweiler, Hannes 2016. Cooperation of local motions in the Hsp90 molecular chaperone ATPase mechanism. Nature Chemical Biology, Vol. 12, Issue. 8, p. 628.


    Shrestha, Liza Patel, Hardik J. and Chiosis, Gabriela 2016. Chemical Tools to Investigate Mechanisms Associated with HSP90 and HSP70 in Disease. Cell Chemical Biology, Vol. 23, Issue. 1, p. 158.


    Sung, Nuri Lee, Jungsoon Kim, Ji-Hyun Chang, Changsoo Joachimiak, Andrzej Lee, Sukyeong and Tsai, Francis T. F. 2016. Mitochondrial Hsp90 is a ligand-activated molecular chaperone coupling ATP binding to dimer closure through a coiled-coil intermediate. Proceedings of the National Academy of Sciences, Vol. 113, Issue. 11, p. 2952.


    Verba, K. A. Wang, R. Y.-R. Arakawa, A. Liu, Y. Shirouzu, M. Yokoyama, S. and Agard, D. A. 2016. Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase. Science, Vol. 352, Issue. 6293, p. 1542.


    Vettoretti, Gerolamo Moroni, Elisabetta Sattin, Sara Tao, Jiahui Agard, David A. Bernardi, Anna and Colombo, Giorgio 2016. Molecular Dynamics Simulations Reveal the Mechanisms of Allosteric Activation of Hsp90 by Designed Ligands. Scientific Reports, Vol. 6, p. 23830.


    Wieder, Marcus Perricone, Ugo Seidel, Thomas Boresch, Stefan and Langer, Thierry 2016. Comparing pharmacophore models derived from crystal structures and from molecular dynamics simulations. Monatshefte für Chemie - Chemical Monthly, Vol. 147, Issue. 3, p. 553.


    Yim, Kendrick H. Prince, Thomas L. Qu, Shiwei Bai, Fang Jennings, Patricia A. Onuchic, José N. Theodorakis, Emmanuel A. and Neckers, Leonard 2016. Gambogic acid identifies an isoform-specific druggable pocket in the middle domain of Hsp90β. Proceedings of the National Academy of Sciences, p. 201606655.


    Batista, Fernanda A.H. Almeida, Glessler S. Seraphim, Thiago V. Silva, Kelly P. Murta, Silvane M.F. Barbosa, Leandro R.S. and Borges, Júlio C. 2015. Identification of two p23 co-chaperone isoforms inLeishmania braziliensisexhibiting similar structures and Hsp90 interaction properties despite divergent stabilities. FEBS Journal, Vol. 282, Issue. 2, p. 388.


    Genest, Olivier Hoskins, Joel R. Kravats, Andrea N. Doyle, Shannon M. and Wickner, Sue 2015. Hsp70 and Hsp90 of E. coli Directly Interact for Collaboration in Protein Remodeling. Journal of Molecular Biology, Vol. 427, Issue. 24, p. 3877.


    Haslbeck, Veronika Eckl, Julia M. Drazic, Adrian Rutz, Daniel A. Lorenz, Oliver R. Zimmermann, Kerstin Kriehuber, Thomas Lindemann, Claudia Madl, Tobias and Richter, Klaus 2015. The activity of protein phosphatase 5 towards native clients is modulated by the middle- and C-terminal domains of Hsp90. Scientific Reports, Vol. 5, p. 17058.


    Krishnan, Asha Sreeremya, Thadathil S. Mohamed, A. Peer Hareesh, Unnikrishnan Saraswathy and Ghosh, Swapankumar 2015. Concentration quenching in cerium oxide dispersions via a Förster resonance energy transfer mechanism facilitates the identification of fatty acids. RSC Adv., Vol. 5, Issue. 30, p. 23965.


    Kumalo, Hezekiel M. Bhakat, Soumendranath and Soliman, Mahmoud E. 2015. Heat-Shock Protein 90 (Hsp90) as Anticancer Target for Drug Discovery: An Ample Computational Perspective. Chemical Biology & Drug Design, Vol. 86, Issue. 5, p. 1131.


    ×

Conformational dynamics of the molecular chaperone Hsp90

  • Kristin A. Krukenberg (a1), Timothy O. Street (a1), Laura A. Lavery (a1) and David A. Agard (a1) (a2)
  • DOI: http://dx.doi.org/10.1017/S0033583510000314
  • Published online: 18 March 2011
Abstract
Abstract

The ubiquitous molecular chaperone Hsp90 makes up 1–2% of cytosolic proteins and is required for viability in eukaryotes. Hsp90 affects the folding and activation of a wide variety of substrate proteins including many involved in signaling and regulatory processes. Some of these substrates are implicated in cancer and other diseases, making Hsp90 an attractive drug target. Structural analyses have shown that Hsp90 is a highly dynamic and flexible molecule that can adopt a wide variety of structurally distinct states. 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 only shift the equilibria between a pre-existing set of conformational states. For bacterial, yeast and human Hsp90, there is a conserved three-state (apo–ATP–ADP) conformational cycle; however; the equilibria between states are species specific. In eukaryotes, cytosolic co-chaperones regulate the in vivo dynamic behavior of Hsp90 by shifting conformational equilibria and affecting the kinetics of structural changes and ATP hydrolysis. In this review, we discuss the structural and biochemical studies leading to our current understanding of the conformational dynamics of Hsp90, as well as the roles that nucleotide, co-chaperones, post-translational modification and substrates play. This view of Hsp90's conformational dynamics was enabled by the use of multiple complementary structural methods including, crystallography, small-angle X-ray scattering (SAXS), electron microscopy, Förster resonance energy transfer (FRET) and NMR. Finally, we discuss the effects of Hsp90 inhibitors on conformation and the potential for developing small molecules that inhibit Hsp90 by disrupting the conformational dynamics.

Copyright
Corresponding author
*Author for correspondence: D. A. Agard, Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA. Tel.: 415-476-2521; Fax: 41-476-1902; Email: agard@msg.ucsf.edu
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

A. T. Alexandrescu , C. Abeygunawardana & D. Shortle (1994). Structure and dynamics of a denatured 131-residue fragment of staphylococcal nuclease: a heteronuclear NMR study. Biochemistry 33, 10631072.

S. J. Arlander , S. J. Felts , J. M. Wagner , B. Stensgard , D. O. Toft & L. M. Karnitz (2006). Chaperoning checkpoint kinase 1 (Chk1), an Hsp90 client, with purified chaperones. Journal of Biological Chemistry 281, 29892998.

G. Chiosis , B. Lucas , H. Huezo , D. Solit , A. Basso & N. Rosen (2003). Development of purine-scaffold small molecule inhibitors of Hsp90. Current Cancer Drug Targets 3, 371376.

K. D. Dittmar & W. B. Pratt (1997). Folding of the glucocorticoid receptor by the reconstituted Hsp90-based chaperone machinery. The initial hsp90.p60.hsp70-dependent step is sufficient for creating the steroid binding conformation. Journal of Biological Chemistry 272, 1304713054.

H. L. Forsythe , J. L. Jarvis , J. W. Turner , L. W. Elmore & S. E. Holt (2001). Stable association of hsp90 and p23, but Not hsp70, with active human telomerase. Journal of Biological Chemistry 276, 1557115574.

P. Gomez-Puertas , J. Martin-Benito , J. L. Carrascosa , K. R. Willison & J. M. Valpuesta (2004). The substrate recognition mechanisms in chaperonins. Journal of Molecular Recognition 17, 8594.

C. Graf , M. Stankiewicz , G. Kramer & M. P. Mayer (2009). Spatially and kinetically resolved changes in the conformational dynamics of the Hsp90 chaperone machine. EMBO Journal 28, 602613.

J. P. Grenert , B. D. Johnson & D. O. Toft (1999). The importance of ATP binding and hydrolysis by hsp90 in formation and function of protein heterocomplexes. Journal of Biological Chemistry 274, 1752517533.

A. Harst , H. Lin & W. M. Obermann (2005). Aha1 competes with Hop, p50 and p23 for binding to the molecular chaperone Hsp90 and contributes to kinase and hormone receptor activation. Biochemical Journal 387, 789796.

V. D. Kekatpure , A. J. Dannenberg & K. Subbaramaiah (2009). HDAC6 modulates Hsp90 chaperone activity and regulates activation of ary1 hydrocarbon receptor signaling. J Biol Chem 284, 74367445.

P. Lee , J. Rao , A. Fliss , E. Yang , S. Garrett & A. J. Caplan (2002). The Cdc37 protein kinase-binding domain is sufficient for protein kinase activity and cell viability. Journal of Cell Biology 159, 10511059.

M. G. Marcu , A. Chadli , I. Bouhouche , M. Catelli & L. M. Neckers (2000a). The heat shock protein 90 antagonist novobiocin interacts with a previously unrecognized ATP-binding domain in the carboxyl terminus of the chaperone. Journal of Biological Chemistry 275, 3718137186.

S. H. McLaughlin , H. W. Smith & S. E. Jackson (2002). Stimulation of the weak ATPase activity of human hsp90 by a client protein. Journal of Molecular Biology 315, 787798.

S. H. McLaughlin , F. Sobott , Z. P. Yao , W. Zhang , P. R. Nielsen , J. G. Grossmann , E. D. Laue , C. V. Robinson & S. E. Jackson (2006). The co-chaperone p23 arrests the Hsp90 ATPase cycle to trap client proteins. Journal of Molecular Biology 356, 746758.

S. H. Millson , A. W. Truman , F. Wolfram , V. King , B. Panaretou , C. Prodromou , L. H. Pearl & P. W. Piper (2004). Investigating the protein-protein interactions of the yeast Hsp90 chaperone system by two-hybrid analysis: potential uses and limitations of this approach. Cell Stress and Chaperones 9, 359368.

H. Ogiso , N. Kagi , E. Matsumoto , M. Nishimoto , R. Arai , M. Shirouzu , J. Mimura , Y. Fujii-Kuriyama & S. Yokoyama . (2004). Phosphorylation analysis of 90 kDa heat shock protein within the cytosolic arylhydrocarbon receptor complex. Biochemistry 43, 1551015519.

Y. Nishiya , K. Shibata , S. Saito , K. Yano , C. Oneyama , H. Nakano & S. V. Sharma (2009). Drug-target identification from total cellular lysate by drug-induced conformational changes. Analytical Biochemistry 385, 314320.

S. C. Onuoha , E. T. Coulstock , J. G. Grossmann & S. E. Jackson (2008). Structural studies on the co-chaperone Hop and its complexes with Hsp90. Journal of Molecular Biology 379, 732744.

C. M. Palermo , C. A. Westlake & T. A. Gasiewicz (2005). Epigallocatechin gallate inhibits aryl hydrocarbon receptor gene transcription through an indirect mechanism involving binding to a 90 kDa heat shock protein. Biochemistry 44, 50415052.

J. J. Phillips , Z. P. Yao , W. Zhang , S. McLaughlin , E. D. Laue , C. V. Robinson & S. E. Jackson (2007). Conformational dynamics of the molecular chaperone Hsp90 in complexes with a co-chaperone and anticancer drugs. Journal of Molecular Biology 372, 11891203.

M. Retzlaff , F. Hagn , L. Mitschke , M. Hessling , F. Gugel , H. Kessler , K. Richter & J. Buchner (2010). Asymmetric activation of the hsp90 dimer by its cochaperone aha1. Molecular Cell 37, 344354.

K. Richter , P. Muschler , O. Hainzl , J. Reinstein & J. Buchner (2003). Sti1 is a non-competitive inhibitor of the Hsp90 ATPase. Binding prevents the N-terminal dimerization reaction during the atpase cycle. Journal of Biological Chemistry 278, 1032810333.

B. T. Scroggins , K. Robzyk , D. Wang , M. G. Marcu , S. Tsutsumi , K. Beebe , R. J. Cotter , S. Felts , D. Toft , L. Karnitz , N. Rosen & L. Neckers (2007). An acetylation site in the middle domain of Hsp90 regulates chaperone function. Mol Cell 25, 151159.

A. K. Shiau , S. F. Harris , D. R. Southworth & D. A. Agard (2006). Structural Analysis of E. coli hsp90 reveals dramatic nucleotide-dependent conformational rearrangements. Cell 127, 329340.

C. E. Stebbins , A. A. Russo , C. Schneider , N. Rosen , F. U. Hartl & N. P. Pavletich (1997). Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent. Cell 89, 239250.

W. Sullivan , B. Stensgard , G. Caucutt , B. Bartha , N. McMahon , E. S. Alnemri , G. Litwack & D. Toft (1997). Nucleotides and two functional states of hsp90. Journal of Biological Chemistry 272, 80078012.

H. Wegele , P. Muschler , M. Bunck , J. Reinstein & J. Buchner (2003). Dissection of the contribution of individual domains to the ATPase mechanism of Hsp90. Journal of Biological Chemistry 278, 3930339310.

L. Whitesell , E. G. Mimnaugh , B. De Costa , C. E. Myers & L. M. Neckers (1994). Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proceedings of the National Academy of Sciences, USA 91, 83248328.

T. Weikl , P. Muschler , K. Richter , T. Veit , J. Reinstein & J. Buchner (2000). C-terminal regions of Hsp90 are important for trapping the nucleotide during the ATPase cycle. J Mol Biol 303, 583592.

H. Wiech , J. Buchner , R. Zimmermann & U. Jakob (1992). Hsp90 chaperones protein folding in vitro. Nature 358, 169170.

P. Workman (2004). Combinatorial attack on multistep oncogenesis by inhibiting the Hsp90 molecular chaperone. Cancer Letters 206, 149157.

W. Zhang , M. Hirshberg , S. H. McLaughlin , G. A. Lazar , J. G. Grossmann , P. R. Nielsen , F. Sobott , C. V. Robinson , S. E. Jackson & E. D. Laue (2004). Biochemical and structural studies of the interaction of Cdc37 with Hsp90. Journal of Molecular Biology 340, 891907.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Quarterly Reviews of Biophysics
  • ISSN: 0033-5835
  • EISSN: 1469-8994
  • URL: /core/journals/quarterly-reviews-of-biophysics
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×