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The HSP90 chaperone machinery

Key Points

  • Heat shock protein 90 (HSP90) is a molecular chaperone that is conserved from bacteria to humans and facilitates the maturation of substrates (or clients) that are involved in many different cellular pathways. HSP90 clients include, among others, kinases, transcription factors, steroid hormone receptors and E3 ubiquitin ligases.

  • The highly dynamic conformational changes in the HSP90 dimer are regulated by a set of co-chaperones that bind to HSP90, often in different phases of its ATPase cycle. Co-chaperones modulate the rate of ATP hydrolysis by HSP90, stabilize certain conformational states or are involved in client recruitment. Some co-chaperones introduce asymmetry in the symmetric HSP90 dimer.

  • HSP90 binds to clients in different conformations. Novel insights into client maturation have revealed that clients form contacts mainly with the middle domain of HSP90, but also make contacts with the amino-terminal and carboxy-terminal domains.

  • HSP90 clients are functionally and structurally diverse. Within this broad range of clients, intrinsic instability and low folding cooperativity seem to dictate the requirement for the chaperone activity of HSP90.

  • The pleiotropic effects of HSP90 on diverse client proteins means that HSP90 is implicated in many diseases, most prominently cancer, neurodegenerative diseases and infectious diseases that are caused by viruses and protozoa.

  • A number of HSP90 inhibitors have been identified that target the ATP-binding site or the carboxy-terminal domain. A number of these are currently being evaluated in clinical trials.

Abstract

The heat shock protein 90 (HSP90) chaperone machinery is a key regulator of proteostasis under both physiological and stress conditions in eukaryotic cells. As HSP90 has several hundred protein substrates (or 'clients'), it is involved in many cellular processes beyond protein folding, which include DNA repair, development, the immune response and neurodegenerative disease. A large number of co-chaperones interact with HSP90 and regulate the ATPase-associated conformational changes of the HSP90 dimer that occur during the processing of clients. Recent progress has allowed the interactions of clients with HSP90 and its co-chaperones to be defined. Owing to the importance of HSP90 in the regulation of many cellular proteins, it has become a promising drug target for the treatment of several diseases, which include cancer and diseases associated with protein misfolding.

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Figure 1: The function, structure and conformational cycle of HSP90.
Figure 2: The binding of co-chaperones to HSP90.
Figure 3: The binding of clients to HSP90.
Figure 4: Co-chaperone regulation of client activation.

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References

  1. Ritossa, F. Discovery of the heat shock response. Cell Stress Chaperones 1, 97–98 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Pratt, W. B. & Toft, D. O. Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr. Rev. 18, 306–360 (1997).

    CAS  PubMed  Google Scholar 

  3. Brugge, J. S. & Erikson, R. L. Identification of a transformation-specific antigen induced by an avian sarcoma virus. Nature 269, 346–348 (1977).

    Article  CAS  PubMed  Google Scholar 

  4. Borkovich, K. A., Farrelly, F. W., Finkelstein, D. B., Taulien, J. & Lindquist, S. Hsp82 is an essential protein that is required in higher concentrations for growth of cells at higher temperatures. Mol. Cell. Biol. 9, 3919–3930 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Shen, Y. et al. Essential role of the first intron in the transcription of hsp90βgene. FEBS Lett. 413, 92–98 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Zhang, S. L. et al. Regulation of human hsp90alpha gene expression. FEBS Lett. 444, 130–135 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Chen, B., Zhong, D. & Monteiro, A. Comparative genomics and evolution of the HSP90 family of genes across all kingdoms of organisms. BMC Genomics 7, 156 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Johnson, J. L. Evolution and function of diverse Hsp90 homologs and cochaperone proteins. Biochim. Biophys. Acta 1823, 607–613 (2012).

    Article  CAS  PubMed  Google Scholar 

  9. Felts, S. J. et al. The hsp90-related protein TRAP1 is a mitochondrial protein with distinct functional properties. J. Biol. Chem. 275, 3305–3312 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Willmund, F. & Schroda, M. HEAT SHOCK PROTEIN 90C is a bona fide Hsp90 that interacts with plastidic HSP70B in Chlamydomonas reinhardtii. Plant Physiol. 138, 2310–2322 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rutherford, S. L. & Lindquist, S. Hsp90 as a capacitor for morphological evolution. Nature 396, 336–342 (1998). Shows that inhibition of the HSP90 orthologue Hsp83 in Drosophila results in a burst of phenotypic variation, which suggests that HSP90 controls the evolution of traits.

    Article  CAS  PubMed  Google Scholar 

  12. Queitsch, C., Sangster, T. A. & Lindquist, S. Hsp90 as a capacitor of phenotypic variation. Nature 417, 618–624 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Jarosz, D. F. & Lindquist, S. Hsp90 and environmental stress transform the adaptive value of natural genetic variation. Science 330, 1820–1824 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rohner, N. et al. Cryptic variation in morphological evolution: HSP90 as a capacitor for loss of eyes in cavefish. Science 342, 1372–1375 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mayer, M. P. & Le Breton, L. Hsp90: breaking the symmetry. Mol. Cell 58, 8–20 (2015).

    Article  CAS  PubMed  Google Scholar 

  16. Wayne, N. & Bolon, D. N. Dimerization of Hsp90 is required for in vivo function. Design and analysis of monomers and dimers. J. Biol. Chem. 282, 35386–35395 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Prodromou, C. et al. Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell 90, 65–75 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Harris, S. F., Shiau, A. K. & Agard, D. A. The crystal structure of the carboxy-terminal dimerization domain of htpG, the Escherichia coli Hsp90, reveals a potential substrate binding site. Structure 12, 1087–1097 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Buchner, J. Hsp90 & co. — a holding for folding. Trends Biochem. Sci. 24, 136–141 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Hainzl, O., Lapina, M. C., Buchner, J. & Richter, K. The charged linker region is an important regulator of Hsp90 function. J. Biol. Chem. 284, 22559–22567 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jahn, M. et al. The charged linker of the molecular chaperone Hsp90 modulates domain contacts and biological function. Proc. Natl Acad. Sci. USA 111, 17881–17886 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zuehlke, A. D. & Johnson, J. L. Chaperoning the chaperone: a role for the co-chaperone Cpr7 in modulating Hsp90 function in Saccharomyces cerevisiae. Genetics 191, 805–814 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tsutsumi, S. et al. Charged linker sequence modulates eukaryotic heat shock protein 90 (Hsp90) chaperone activity. Proc. Natl Acad. Sci. USA 109, 2937–2942 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Shiau, A. K., Harris, S. F., Southworth, D. R. & Agard, D. A. Structural analysis of E. coli hsp90 reveals dramatic nucleotide-dependent conformational rearrangements. Cell 127, 329–340 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Dollins, D. E., Warren, J. J., Immormino, R. M. & Gewirth, D. T. Structures of GRP94-nucleotide complexes reveal mechanistic differences between the hsp90 chaperones. Mol. Cell 28, 41–56 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hellenkamp, B., Wortmann, P., Kandzia, F., Zacharias, M. & Hugel, T. Multidomain structure and correlated dynamics determined by self-consistent FRET networks. Nat. Methods 14, 174–180 (2017).

    Article  CAS  PubMed  Google Scholar 

  27. Ratzke, C., Nguyen, M. N., Mayer, M. P. & Hugel, T. From a ratchet mechanism to random fluctuations evolution of Hsp90's mechanochemical cycle. J. Mol. Biol. 423, 462–471 (2012).

    Article  CAS  PubMed  Google Scholar 

  28. Mickler, M., Hessling, M., Ratzke, C., Buchner, J. & Hugel, T. The large conformational changes of Hsp90 are only weakly coupled to ATP hydrolysis. Nat. Struct. Mol. Biol. 16, 281–286 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Graf, C., Stankiewicz, M., Kramer, G. & Mayer, M. P. Spatially and kinetically resolved changes in the conformational dynamics of the Hsp90 chaperone machine. EMBO J. 28, 602–613 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Dutta, R. & Inouye, M. GHKL, an emergent ATPase/kinase superfamily. Trends Biochem. Sci. 25, 24–28 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. Scheibel, T. et al. ATP-binding properties of human Hsp90. J. Biol. Chem. 272, 18608–18613 (1997).

    Article  CAS  PubMed  Google Scholar 

  32. McLaughlin, S. H., Smith, H. W. & Jackson, S. E. Stimulation of the weak ATPase activity of human hsp90 by a client protein. J. Mol. Biol. 315, 787–798 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Stebbins, C. E. et al. Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent. Cell 89, 239–250 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Hessling, M., Richter, K. & Buchner, J. Dissection of the ATP-induced conformational cycle of the molecular chaperone Hsp90. Nat. Struct. Mol. Biol. 16, 287–293 (2009). Förster resonance energy transfer (FRET) analyses reveal that the conformational transitions that lead to an ATPase-active closed conformation are rate-limiting and can be targeted by co-chaperones.

    Article  CAS  PubMed  Google Scholar 

  35. Prodromou, C. et al. The ATPase cycle of Hsp90 drives a molecular 'clamp' via transient dimerization of the N-terminal domains. EMBO J. 19, 4383–4392 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cunningham, C. N., Krukenberg, K. A. & Agard, D. A. Intra- and intermonomer interactions are required to synergistically facilitate ATP hydrolysis in Hsp90. J. Biol. Chem. 283, 21170–21178 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Meyer, P. et al. Structural and functional analysis of the middle segment of hsp90: implications for ATP hydrolysis and client protein and cochaperone interactions. Mol. Cell 11, 647–658 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Obermann, W. M., Sondermann, H., Russo, A. A., Pavletich, N. P. & Hartl, F. U. In vivo function of Hsp90 is dependent on ATP binding and ATP hydrolysis. J. Cell Biol. 143, 901–910 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Panaretou, B. et al. ATP binding and hydrolysis are essential to the function of the Hsp90 molecular chaperone in vivo. EMBO J. 17, 4829–4836 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mishra, P. & Bolon, D. N. Designed Hsp90 heterodimers reveal an asymmetric ATPase-driven mechanism in vivo. Mol. Cell 53, 344–350 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zierer, B. K. et al. Importance of cycle timing for the function of the molecular chaperone Hsp90. Nat. Struct. Mol. Biol. 23, 1020–1028 (2016). Shows that for in vivo function in yeast, the amount of time that HSP90 spends in different steps of the cycle, and not the overall speed, is important.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Prodromou, C. Mechanisms of Hsp90 regulation. Biochem. J. 473, 2439–2452 (2016).

    Article  CAS  PubMed  Google Scholar 

  43. Solis, E. J. et al. Defining the essential function of yeast Hsf1 reveals a compact transcriptional program for maintaining eukaryotic proteostasis. Mol. Cell 63, 60–71 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Voellmy, R. & Boellmann, F. Chaperone regulation of the heat shock protein response. Adv. Exp. Med. Biol. 594, 89–99 (2007).

    Article  PubMed  Google Scholar 

  45. Rohl, A., Rohrberg, J. & Buchner, J. The chaperone Hsp90: changing partners for demanding clients. Trends Biochem. Sci. 38, 253–262 (2013).

    Article  PubMed  CAS  Google Scholar 

  46. Scroggins, B. T. & Neckers, L. Post-translational modification of heat-shock protein 90: impact on chaperone function. Expert Opin. Drug Discov. 2, 1403–1414 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Soroka, J. et al. Conformational switching of the molecular chaperone Hsp90 via regulated phosphorylation. Mol. Cell 45, 517–528 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. Mollapour, M. & Neckers, L. Post-translational modifications of Hsp90 and their contributions to chaperone regulation. Biochim. Biophys. Acta 1823, 648–655 (2012).

    Article  CAS  PubMed  Google Scholar 

  49. Zhao, Y. G. et al. Hsp90 phosphorylation is linked to its chaperoning function. Assembly of the reovirus cell attachment protein. J. Biol. Chem. 276, 32822–32827 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Mollapour, M. et al. Threonine 22 phosphorylation attenuates Hsp90 interaction with cochaperones and affects its chaperone activity. Mol. Cell 41, 672–681 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mollapour, M. et al. Swe1Wee1-dependent tyrosine phosphorylation of Hsp90 regulates distinct facets of chaperone function. Mol. Cell 37, 333–343 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wandinger, S. K., Suhre, M. H., Wegele, H. & Buchner, J. The phosphatase Ppt1 is a dedicated regulator of the molecular chaperone Hsp90. EMBO J. 25, 367–376 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kovacs, J. J. et al. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol. Cell 18, 601–607 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Bali, P. et al. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J. Biol. Chem. 280, 26729–26734 (2005).

    Article  CAS  PubMed  Google Scholar 

  55. Scroggins, B. T. et al. An acetylation site in the middle domain of Hsp90 regulates chaperone function. Mol. Cell 25, 151–159 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Garcia-Cardena, G. et al. Dynamic activation of endothelial nitric oxide synthase by Hsp90. Nature 392, 821–824 (1998).

    Article  CAS  PubMed  Google Scholar 

  57. Martinez-Ruiz, A. et al. S-Nitrosylation of Hsp90 promotes the inhibition of its ATPase and endothelial nitric oxide synthase regulatory activities. Proc. Natl Acad. Sci. USA 102, 8525–8530 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Retzlaff, M. et al. Hsp90 is regulated by a switch point in the C-terminal domain. EMBO Rep. 10, 1147–1153 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Das, A. K., Cohen, P. W. & Barford, D. The structure of the tetratricopeptide repeats of protein phosphatase 5: implications for TPR-mediated protein-protein interactions. EMBO J. 17, 1192–1199 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Scheufler, C. et al. Structure of TPR domain-peptide complexes: critical elements in the assembly of the Hsp70-Hsp90 multichaperone machine. Cell 101, 199–210 (2000). The structure of a HOP–TPR–peptide complex explains how TPR domains participate in the assembly of the HSP70–HSP90 multichaperone complex.

    Article  CAS  PubMed  Google Scholar 

  61. Schmid, A. B. et al. The architecture of functional modules in the Hsp90 co-chaperone Sti1/Hop. EMBO J. 31, 1506–1517 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Johnson, B. D., Schumacher, R. J., Ross, E. D. & Toft, D. O. Hop modulates Hsp70/Hsp90 interactions in protein folding. J. Biol. Chem. 273, 3679–3686 (1998).

    Article  CAS  PubMed  Google Scholar 

  63. Wegele, H., Wandinger, S. K., Schmid, A. B., Reinstein, J. & Buchner, J. Substrate transfer from the chaperone Hsp70 to Hsp90. J. Mol. Biol. 356, 802–811 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Li, J., Richter, K. & Buchner, J. Mixed Hsp90-cochaperone complexes are important for the progression of the reaction cycle. Nat. Struct. Mol. Biol. 18, 61–66 (2011). Shows that defined combinations of co-chaperones associate with specific conformational states of Hsp90, which results in an ordered progression of co-chaperone exchange during the functional cycle.

    Article  PubMed  CAS  Google Scholar 

  65. Richter, K., Muschler, P., Hainzl, O., Reinstein, J. & Buchner, J. Sti1 is a non-competitive inhibitor of the Hsp90 ATPase. Binding prevents the N-terminal dimerization reaction during the atpase cycle. J. Biol. Chem. 278, 10328–10333 (2003).

    Article  CAS  PubMed  Google Scholar 

  66. Prodromou, C. et al. Regulation of Hsp90 ATPase activity by tetratricopeptide repeat (TPR)-domain co-chaperones. EMBO J. 18, 754–762 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Rohl, A. et al. Hsp90 regulates the dynamics of its cochaperone Sti1 and the transfer of Hsp70 between modules. Nat. Commun. 6, 6655 (2015).

    Article  PubMed  CAS  Google Scholar 

  68. Lee, C. T., Graf, C., Mayer, F. J., Richter, S. M. & Mayer, M. P. Dynamics of the regulation of Hsp90 by the co-chaperone Sti1. EMBO J. 31, 1518–1528 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Alvira, S. et al. Structural characterization of the substrate transfer mechanism in Hsp70/Hsp90 folding machinery mediated by Hop. Nat. Commun. 5, 5484 (2014).

    Article  PubMed  Google Scholar 

  70. Rohl, A. et al. Hop/Sti1 phosphorylation inhibits its co-chaperone function. EMBO Rep. 16, 240–249 (2015).

    Article  PubMed  CAS  Google Scholar 

  71. Beraldo, F. H. et al. Stress-inducible phosphoprotein 1 has unique cochaperone activity during development and regulates cellular response to ischemia via the prion protein. FASEB J. 27, 3594–3607 (2013).

    Article  CAS  PubMed  Google Scholar 

  72. Chang, H. C., Nathan, D. F. & Lindquist, S. In vivo analysis of the Hsp90 cochaperone Sti1 (p60). Mol. Cell. Biol. 17, 318–325 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Genest, O., Hoskins, J. R., Kravats, A. N., Doyle, S. M. & Wickner, S. Hsp70 and Hsp90 of E. coli directly interact for collaboration in protein remodeling. J. Mol. Biol. 427, 3877–3889 (2015). Demonstrates that bacterial HSP90 and HSP70 bind to each other directly, and that this interaction is stabilized by the binding of client proteins, which explains how client transfer can occur in the absence of co-chaperones.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Vaughan, C. K. et al. Hsp90-dependent activation of protein kinases is regulated by chaperone-targeted dephosphorylation of Cdc37. Mol. Cell 31, 886–895 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Riggs, D. L. et al. Noncatalytic role of the FKBP52 peptidyl-prolyl isomerase domain in the regulation of steroid hormone signaling. Mol. Cell. Biol. 27, 8658–8669 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bose, S., Weikl, T., Bugl, H. & Buchner, J. Chaperone function of Hsp90-associated proteins. Science 274, 1715–1717 (1996).

    Article  CAS  PubMed  Google Scholar 

  77. Freeman, B. C., Toft, D. O. & Morimoto, R. I. Molecular chaperone machines: chaperone activities of the cyclophilin Cyp-40 and the steroid aporeceptor-associated protein p23. Science 274, 1718–1720 (1996).

    Article  CAS  PubMed  Google Scholar 

  78. Roe, S. M. et al. The mechanism of Hsp90 regulation by the protein kinase-specific cochaperone p50(cdc37). Cell 116, 87–98 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Siligardi, G. et al. Regulation of Hsp90 ATPase activity by the co-chaperone Cdc37p/p50cdc37. J. Biol. Chem. 277, 20151–20159 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Verba, K. A. et al. Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase. Science 352, 1542–1547 (2016). The remarkable electron microscopy structure of the HSP90–CDC37–CDK4 complex explains in atomic detail how HSP90 affects client kinase structure and how the co-chaperone CDC37 interacts with the client and HSP90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Eckl, J. M. et al. Cdc37 (cell division cycle 37) restricts Hsp90 (heat shock protein 90) motility by interaction with N-terminal and middle domain binding sites. J. Biol. Chem. 288, 16032–16042 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Eckl, J. M. et al. Hsp90·Cdc37 complexes with protein kinases form cooperatively with multiple distinct interaction sites. J. Biol. Chem. 290, 30843–30854 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Panaretou, B. et al. Activation of the ATPase activity of hsp90 by the stress-regulated cochaperone aha1. Mol. Cell 10, 1307–1318 (2002).

    Article  CAS  PubMed  Google Scholar 

  84. Meyer, P. et al. Structural basis for recruitment of the ATPase activator Aha1 to the Hsp90 chaperone machinery. EMBO J. 23, 1402–1410 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Retzlaff, M. et al. Asymmetric activation of the hsp90 dimer by its cochaperone aha1. Mol. Cell 37, 344–354 (2010).

    Article  CAS  PubMed  Google Scholar 

  86. Koulov, A. V. et al. Biological and structural basis for Aha1 regulation of Hsp90 ATPase activity in maintaining proteostasis in the human disease cystic fibrosis. Mol. Biol. Cell 21, 871–884 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Li, J., Richter, K., Reinstein, J. & Buchner, J. Integration of the accelerator Aha1 in the Hsp90 co-chaperone cycle. Nat. Struct. Mol. Biol. 20, 326–331 (2013).

    Article  PubMed  CAS  Google Scholar 

  88. Lorenz, O. R. et al. Modulation of the hsp90 chaperone cycle by a stringent client protein. Mol. Cell 53, 941–953 (2014). Reconstitution of the interaction of GR with HSP90 in vitro provides structural and functional insight into the interaction of HSP90 with a stringent client.

    Article  CAS  PubMed  Google Scholar 

  89. Ali, M. M. et al. Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex. Nature 440, 1013–1017 (2006). The crystal structure of a complex containing full-length HSP90 in the closed state, p23 and ATP, provides important insight into the structural organization of HSP90 and the structural rearrangement that leads to NTD dimerization.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Richter, K., Walter, S. & Buchner, J. The co-chaperone Sba1 connects the ATPase reaction of Hsp90 to the progression of the chaperone cycle. J. Mol. Biol. 342, 1403–1413 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Johnson, J. L. & Toft, D. O. A novel chaperone complex for steroid receptors involving heat shock proteins, immunophilins, and p23. J. Biol. Chem. 269, 24989–24993 (1994).

    Article  CAS  PubMed  Google Scholar 

  92. Weaver, A. J., Sullivan, W. P., Felts, S. J., Owen, B. A. & Toft, D. O. Crystal structure and activity of human p23, a heat shock protein 90 co-chaperone. J. Biol. Chem. 275, 23045–23052 (2000).

    Article  CAS  PubMed  Google Scholar 

  93. Weikl, T., Abelmann, K. & Buchner, J. An unstructured C-terminal region of the Hsp90 co-chaperone p23 is important for its chaperone function. J. Mol. Biol. 293, 685–691 (1999).

    Article  CAS  PubMed  Google Scholar 

  94. Zelin, E., Zhang, Y., Toogun, O. A., Zhong, S. & Freeman, B. C. The p23 molecular chaperone and GCN5 acetylase jointly modulate protein-DNA dynamics and open chromatin status. Mol. Cell 48, 459–470 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Echtenkamp, F. J. et al. Global functional map of the p23 molecular chaperone reveals an extensive cellular network. Mol. Cell 43, 229–241 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Echtenkamp, F. J. et al. Hsp90 and p23 molecular chaperones control chromatin architecture by maintaining the functional pool of the RSC chromatin remodeler. Mol. Cell 64, 888–899 (2016). Shows that the co-chaperone p23 modulates genome-wide protein–DNA binding dynamics through its intrinsic chaperone activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kitagawa, K., Skowyra, D., Elledge, S. J., Harper, J. W. & Hieter, P. SGT1 encodes an essential component of the yeast kinetochore assembly pathway and a novel subunit of the SCF ubiquitin ligase complex. Mol. Cell 4, 21–33 (1999).

    Article  CAS  PubMed  Google Scholar 

  98. Catlett, M. G. & Kaplan, K. B. Sgt1p is a unique co-chaperone that acts as a client adaptor to link Hsp90 to Skp1p. J. Biol. Chem. 281, 33739–33748 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. Mayor, A., Martinon, F., De Smedt, T., Petrilli, V. & Tschopp, J. A crucial function of SGT1 and HSP90 in inflammasome activity links mammalian and plant innate immune responses. Nat. Immunol. 8, 497–503 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Zhang, M. et al. Structural and functional coupling of Hsp90- and Sgt1-centred multi-protein complexes. EMBO J. 27, 2789–2798 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Dolinski, K. J., Cardenas, M. E. & Heitman, J. CNS1 encodes an essential p60/Sti1 homolog in Saccharomyces cerevisiae that suppresses cyclophilin 40 mutations and interacts with Hsp90. Mol. Cell. Biol. 18, 7344–7352 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Marsh, J. A., Kalton, H. M. & Gaber, R. F. Cns1 is an essential protein associated with the hsp90 chaperone complex in Saccharomyces cerevisiae that can restore cyclophilin 40-dependent functions in cpr7Delta cells. Mol. Cell. Biol. 18, 7353–7359 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Tesic, M., Marsh, J. A., Cullinan, S. B. & Gaber, R. F. Functional interactions between Hsp90 and the co-chaperones Cns1 and Cpr7 in Saccharomyces cerevisiae. J. Biol. Chem. 278, 32692–32701 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Hainzl, O., Wegele, H., Richter, K. & Buchner, J. Cns1 is an activator of the Ssa1 ATPase activity. J. Biol. Chem. 279, 23267–23273 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Zhao, R. et al. Molecular chaperone Hsp90 stabilizes Pih1/Nop17 to maintain R2TP complex activity that regulates snoRNA accumulation. J. Cell Biol. 180, 563–578 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Du, S. J., Li, H., Bian, Y. & Zhong, Y. Heat-shock protein 90alpha1 is required for organized myofibril assembly in skeletal muscles of zebrafish embryos. Proc. Natl Acad. Sci. USA 105, 554–559 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Echeverria, P. C., Briand, P. A. & Picard, D. A. Remodeled Hsp90 molecular chaperone ensemble with the novel cochaperone Aarsd1 is required for muscle differentiation. Mol. Cell. Biol. 36, 1310–1321 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Freeman, B. C., Felts, S. J., Toft, D. O. & Yamamoto, K. R. The p23 molecular chaperones act at a late step in intracellular receptor action to differentially affect ligand efficacies. Genes Dev. 14, 422–434 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Liu, B. et al. Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone. Nat. Commun. 1, 79 (2010).

    Article  PubMed  CAS  Google Scholar 

  110. van Anken, E. et al. Efficient IgM assembly and secretion require the plasma cell induced endoplasmic reticulum protein pERp1. Proc. Natl Acad. Sci. USA 106, 17019–17024 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Rosenbaum, M. et al. MZB1 is a GRP94 cochaperone that enables proper immunoglobulin heavy chain biosynthesis upon ER stress. Genes Dev. 28, 1165–1178 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Shimizu, Y., Meunier, L. & Hendershot, L. M. pERp1 is significantly up-regulated during plasma cell differentiation and contributes to the oxidative folding of immunoglobulin. Proc. Natl Acad. Sci. USA 106, 17013–17018 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Chen, S., Prapapanich, V., Rimerman, R. A., Honore, B. & Smith, D. F. Interactions of p60, a mediator of progesterone receptor assembly, with heat shock proteins hsp90 and hsp70. Mol. Endocrinol. 10, 682–693 (1996).

    CAS  PubMed  Google Scholar 

  114. Grammatikakis, N., Lin, J. H., Grammatikakis, A., Tsichlis, P. N. & Cochran, B. H. p50(cdc37) acting in concert with Hsp90 is required for Raf-1 function. Mol. Cell. Biol. 19, 1661–1672 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Taipale, M. et al. Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell 150, 987–1001 (2012). A large-scale in vivo study that provides comprehensive insight into HSP90–client interactions in mammalian cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Taipale, M. et al. A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways. Cell 158, 434–448 (2014). Mass spectrometry and high-throughput assays reveal extensive co-chaperone–chaperone–client networks in human cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Lavery, L. A. et al. Structural asymmetry in the closed state of mitochondrial Hsp90 (TRAP1) supports a two-step ATP hydrolysis mechanism. Mol. Cell 53, 330–343 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ghaemmaghami, S. et al. Global analysis of protein expression in yeast. Nature 425, 737–741 (2003).

    Article  CAS  PubMed  Google Scholar 

  119. Karagoz, G. E. et al. N-Terminal domain of human Hsp90 triggers binding to the cochaperone p23. Proc. Natl Acad. Sci. USA 108, 580–585 (2011).

    Article  CAS  PubMed  Google Scholar 

  120. Southworth, D. R. & Agard, D. A. Client-loading conformation of the Hsp90 molecular chaperone revealed in the cryo-EM structure of the human Hsp90:Hop complex. Mol. Cell 42, 771–781 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Mollapour, M. et al. Asymmetric Hsp90 N domain SUMOylation recruits Aha1 and ATP-competitive inhibitors. Mol. Cell 53, 317–329 (2014). Reports that N-terminal sumoylation, one of the least understood HSP90 PTMs, is important for the recruitment of co-chaperones by HSP90 and the binding of inhibitors to HSP90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Echeverria, P. C., Bernthaler, A., Dupuis, P., Mayer, B. & Picard, D. An interaction network predicted from public data as a discovery tool: application to the Hsp90 molecular chaperone machine. PLoS ONE 6, e26044 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Picard, D. Chaperoning steroid hormone action. Trends Endocrinol. Metab. 17, 229–235 (2006).

    Article  CAS  PubMed  Google Scholar 

  124. Xu, Y. & Lindquist, S. Heat-shock protein hsp90 governs the activity of pp60v-src kinase. Proc. Natl Acad. Sci. USA 90, 7074–7078 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Picard, D. et al. Reduced levels of hsp90 compromise steroid receptor action in vivo. Nature 348, 166–168 (1990). This landmark paper provides important insight into the regulation of SHRs by HSP90 in vivo.

    Article  CAS  PubMed  Google Scholar 

  126. Ding, G. et al. Regulation of ubiquitin-like with plant homeodomain and RING finger domain 1 (UHRF1) protein stability by heat shock protein 90 chaperone machinery. J. Biol. Chem. 291, 20125–20135 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Connell, P. et al. The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins. Nat. Cell Biol. 3, 93–96 (2001).

    Article  CAS  PubMed  Google Scholar 

  128. Xu, W. et al. Chaperone-dependent E3 ubiquitin ligase CHIP mediates a degradative pathway for c-ErbB2/Neu. Proc. Natl Acad. Sci. USA 99, 12847–12852 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Kundrat, L. & Regan, L. Identification of residues on Hsp70 and Hsp90 ubiquitinated by the cochaperone CHIP. J. Mol. Biol. 395, 587–594 (2010).

    Article  CAS  PubMed  Google Scholar 

  130. Ehrlich, E. S. et al. Regulation of Hsp90 client proteins by a Cullin5-RING E3 ubiquitin ligase. Proc. Natl Acad. Sci. USA 106, 20330–20335 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Boczek, E. E. et al. Conformational processing of oncogenic v-Src kinase by the molecular chaperone Hsp90. Proc. Natl Acad. Sci. USA 112, E3189–E3198 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Pratt, W. B. & Dittmar, K. D. Studies with purified chaperones advance the understanding of the mechanism of glucocorticoid receptor-hsp90 heterocomplex assembly. Trends Endocrinol. Metab. 9, 244–252 (1998).

    Article  CAS  PubMed  Google Scholar 

  133. Kirschke, E., Goswami, D., Southworth, D., Griffin, P. R. & Agard, D. A. Glucocorticoid receptor function regulated by coordinated action of the Hsp90 and Hsp70 chaperone cycles. Cell 157, 1685–1697 (2014). Reconstitution of the HSP90–GR–HSP70–HOP interaction in vitro provides structural and functional insight into the chaperoning of a stringent client by HSP70 and HSP90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Ghosh, A. & Stuehr, D. J. Soluble guanylyl cyclase requires heat shock protein 90 for heme insertion during maturation of the NO-active enzyme. Proc. Natl Acad. Sci. USA 109, 12998–13003 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Iwasaki, S. et al. Defining fundamental steps in the assembly of the Drosophila RNAi enzyme complex. Nature 521, 533–536 (2015).

    Article  CAS  PubMed  Google Scholar 

  136. Toogun, O. A., Dezwaan, D. C. & Freeman, B. C. The hsp90 molecular chaperone modulates multiple telomerase activities. Mol. Cell. Biol. 28, 457–467 (2008).

    Article  CAS  PubMed  Google Scholar 

  137. DeZwaan, D. C., Toogun, O. A., Echtenkamp, F. J. & Freeman, B. C. The Hsp82 molecular chaperone promotes a switch between unextendable and extendable telomere states. Nat. Struct. Mol. Biol. 16, 711–716 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Keramisanou, D. et al. Molecular mechanism of protein kinase recognition and sorting by the Hsp90 kinome-specific cochaperone Cdc37. Mol. Cell 62, 260–271 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Falsone, S. F., Leptihn, S., Osterauer, A., Haslbeck, M. & Buchner, J. Oncogenic mutations reduce the stability of SRC kinase. J. Mol. Biol. 344, 281–291 (2004).

    Article  PubMed  CAS  Google Scholar 

  140. Bohen, S. P. & Yamamoto, K. R. Isolation of Hsp90 mutants by screening for decreased steroid receptor function. Proc. Natl Acad. Sci. USA 90, 11424–11428 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Genest, O. et al. Uncovering a region of heat shock protein 90 important for client binding in E. coli and chaperone function in yeast. Mol. Cell 49, 464–473 (2013).

    Article  CAS  PubMed  Google Scholar 

  142. Nathan, D. F. & Lindquist, S. Mutational analysis of Hsp90 function: interactions with a steroid receptor and a protein kinase. Mol. Cell. Biol. 15, 3917–3925 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Blagosklonny, M. V., Toretsky, J., Bohen, S. & Neckers, L. Mutant conformation of p53 translated in vitro or in vivo requires functional HSP90. Proc. Natl Acad. Sci. USA 93, 8379–8383 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Sepehrnia, B., Paz, I. B., Dasgupta, G. & Momand, J. Heat shock protein 84 forms a complex with mutant p53 protein predominantly within a cytoplasmic compartment of the cell. J. Biol. Chem. 271, 15084–15090 (1996).

    Article  CAS  PubMed  Google Scholar 

  145. Nagata, Y. et al. The stabilization mechanism of mutant-type p53 by impaired ubiquitination: the loss of wild-type p53 function and the hsp90 association. Oncogene 18, 6037–6049 (1999).

    Article  CAS  PubMed  Google Scholar 

  146. Whitesell, L., Sutphin, P. D., Pulcini, E. J., Martinez, J. D. & Cook, P. H. The physical association of multiple molecular chaperone proteins with mutant p53 is altered by Geldanamycin, an hsp90-binding agent. Mol. Cell. Biol. 18, 1517–1524 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Muller, L., Schaupp, A., Walerych, D., Wegele, H. & Buchner, J. Hsp90 regulates the activity of wild type p53 under physiological and elevated temperatures. J. Biol. Chem. 279, 48846–48854 (2004).

    Article  PubMed  CAS  Google Scholar 

  148. Wang, C. G. & Chen, J. D. Phosphorylation and hsp90 binding mediate heat shock stabilization of p53. J. Biol. Chem. 278, 2066–2071 (2003).

    Article  CAS  PubMed  Google Scholar 

  149. Walerych, D. et al. Hsp90 chaperones wild-type p53 tumor suppressor protein. J. Biol. Chem. 279, 48836–48845 (2004).

    Article  CAS  PubMed  Google Scholar 

  150. Hagn, F. et al. Structural analysis of the interaction between Hsp90 and the tumor suppressor protein p53. Nat. Struct. Mol. Biol. 18, 1086–1093 (2011).

    Article  CAS  PubMed  Google Scholar 

  151. Park, S. J., Borin, B. N., Martinez-Yamout, M. A. & Dyson, H. J. The client protein p53 adopts a molten globule-like state in the presence of Hsp90. Nat. Struct. Mol. Biol. 18, 537–541 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Park, S. J., Kostic, M. & Dyson, H. J. Dynamic interaction of Hsp90 with its client protein p53. J. Mol. Biol. 411, 158–173 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Rudiger, S., Freund, S. M. V., Veprintsev, D. B. & Fersht, A. R. CRINEPT-TROSY NMR reveals p53 core domain bound in an unfolded form to the chaperone Hsp90. Proc. Natl Acad. Sci. USA 99, 11085–11090 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Karagoz, G. E. et al. Hsp90-Tau complex reveals molecular basis for specificity in chaperone action. Cell 156, 963–974 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Shortle, D. The expanded denatured state: an ensemble of conformations trapped in a locally encoded topological space. Adv. Protein Chem. 62, 1–23 (2002).

    Article  CAS  PubMed  Google Scholar 

  156. Street, T. O., Lavery, L. A. & Agard, D. A. Substrate binding drives large-scale conformational changes in the Hsp90 molecular chaperone. Mol. Cell 42, 96–105 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Sato, T., Minagawa, S., Kojima, E., Okamoto, N. & Nakamoto, H. HtpG, the prokaryotic homologue of Hsp90, stabilizes a phycobilisome protein in the cyanobacterium Synechococcus elongatus PCC 7942. Mol. Microbiol. 76, 576–589 (2010).

    Article  CAS  PubMed  Google Scholar 

  158. Polier, S. et al. ATP-competitive inhibitors block protein kinase recruitment to the Hsp90-Cdc37 system. Nat. Chem. Biol. 9, 307–312 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Eckl, J. M., Daake, M., Schwartz, S. & Richter, K. Nucleotide-free sB-raf is preferentially bound by Hsp90 and Cdc37 in vitro. J. Mol. Biol. 428, 4185–4196 (2016).

    Article  CAS  PubMed  Google Scholar 

  160. Xu, Y., Singer, M. A. & Lindquist, S. Maturation of the tyrosine kinase c-src as a kinase and as a substrate depends on the molecular chaperone Hsp90. Proc. Natl Acad. Sci. USA 96, 109–114 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Mitra, S., Ghosh, B., Gayen, N., Roy, J. & Mandal, A. K. Bipartite role of heat shock protein 90 (Hsp90) keeps CRAF kinase poised for activation. J. Biol. Chem. 291, 24579–24593 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Lachowiec, J., Lemus, T., Borenstein, E. & Queitsch, C. Hsp90 promotes kinase evolution. Mol. Biol. Evol. 32, 91–99 (2015).

    Article  CAS  PubMed  Google Scholar 

  163. Freeman, B. C. & Yamamoto, K. R. Disassembly of transcriptional regulatory complexes by molecular chaperones. Science 296, 2232–2235 (2002).

    Article  CAS  PubMed  Google Scholar 

  164. Oberoi, J. et al. Structural and functional basis of protein phosphatase 5 substrate specificity. Proc. Natl Acad. Sci. USA 113, 9009–9014 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Vartholomaiou, E., Echeverria, P. C. & Picard, D. Unusual suspects in the twilight zone between the Hsp90 interactome and carcinogenesis. Adv. Cancer Res. 129, 1–30 (2016).

    Article  CAS  PubMed  Google Scholar 

  166. Pick, E. et al. High HSP90 expression is associated with decreased survival in breast cancer. Cancer Res. 67, 2932–2937 (2007).

    Article  CAS  PubMed  Google Scholar 

  167. Deb, D., Chakraborti, A. S., Lanyi, A., Troyer, D. A. & Deb, S. Disruption of functions of wild-type p53 by hetero-oligomerization. Int. J. Oncol. 15, 413–422 (1999).

    CAS  PubMed  Google Scholar 

  168. Alexandrova, E. M. et al. Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment. Nature 523, 352–356 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Chiosis, G. & Neckers, L. Tumor selectivity of Hsp90 inhibitors: the explanation remains elusive. ACS Chem. Biol. 1, 279–284 (2006).

    Article  CAS  PubMed  Google Scholar 

  170. Kamal, A. et al. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425, 407–410 (2003).

    Article  CAS  PubMed  Google Scholar 

  171. Rodina, A. et al. The epichaperome is an integrated chaperome network that facilitates tumour survival. Nature 538, 397–401 (2016). Reports that a stable chaperone–co-chaperone network termed the epichaperome is formed upon malignant transformation, which promotes tumour cell survival.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Dickey, C. A. et al. The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. J. Clin. Invest. 117, 648–658 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Evans, C. G., Wisen, S. & Gestwicki, J. E. Heat shock proteins 70 and 90 inhibit early stages of amyloid beta-(1–42) aggregation in vitro. J. Biol. Chem. 281, 33182–33191 (2006).

    Article  CAS  PubMed  Google Scholar 

  174. McLean, P. J., Klucken, J., Shin, Y. & Hyman, B. T. Geldanamycin induces Hsp70 and prevents alpha-synuclein aggregation and toxicity in vitro. Biochem. Biophys. Res. Commun. 321, 665–669 (2004).

    Article  CAS  PubMed  Google Scholar 

  175. Luo, W., Sun, W., Taldone, T., Rodina, A. & Chiosis, G. Heat shock protein 90 in neurodegenerative diseases. Mol. Neurodegener. 5, 24 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. Wang, X. et al. Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell 127, 803–815 (2006).

    Article  CAS  PubMed  Google Scholar 

  177. Geller, R., Taguwa, S. & Frydman, J. Broad action of Hsp90 as a host chaperone required for viral replication. Biochim. Biophys. Acta 1823, 698–706 (2012).

    Article  CAS  PubMed  Google Scholar 

  178. Roy, N., Nageshan, R. K., Ranade, S. & Tatu, U. Heat shock protein 90 from neglected protozoan parasites. Biochim. Biophys. Acta 1823, 707–711 (2012).

    Article  CAS  PubMed  Google Scholar 

  179. Geller, R., Andino, R. & Frydman, J. Hsp90 inhibitors exhibit resistance-free antiviral activity against respiratory syncytial virus. PLoS ONE 8, e56762 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Hombach, A., Ommen, G., Sattler, V. & Clos, J. Leishmania donovani P23 protects parasites against HSP90 inhibitor-mediated growth arrest. Cell Stress Chaperones 20, 673–685 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Wiesgigl, M. & Clos, J. Heat shock protein 90 homeostasis controls stage differentiation in Leishmania donovani. Mol. Biol. Cell 12, 3307–3316 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Karras. G.I. et al.HSP90 shapes the consequences of human genetic variation. Cell 168, 856–866 (2017). Shows that HSP90 is able to buffer the phenotypic consequences of protein variants that are associated with Fanconi anaemia syndrome, which establishes the concept of a chaperone-controlled genetic disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Whitesell, L., Mimnaugh, E. G., De Costa, B., Myers, C. E. & Neckers, L. M. Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc. Natl Acad. Sci. USA 91, 8324–8328 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Roe, S. M. et al. Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin. J. Med. Chem. 42, 260–266 (1999).

    Article  CAS  PubMed  Google Scholar 

  185. Schulte, T. W. et al. Destabilization of Raf-1 by geldanamycin leads to disruption of the Raf-1-MEK-mitogen-activated protein kinase signalling pathway. Mol. Cell. Biol. 16, 5839–5845 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Soga, S., Shiotsu, Y., Akinaga, S. & Sharma, S. V. Development of radicicol analogues. Curr. Cancer Drug Targets 3, 359–369 (2003).

    Article  CAS  PubMed  Google Scholar 

  187. Sharma, S. V., Agatsuma, T. & Nakano, H. Targeting of the protein chaperone, HSP90, by the transformation suppressing agent, radicicol. Oncogene 16, 2639–2645 (1998).

    Article  CAS  PubMed  Google Scholar 

  188. Chiosis, G., Lucas, B., Shtil, A., Huezo, H. & Rosen, N. Development of a purine-scaffold novel class of Hsp90 binders that inhibit the proliferation of cancer cells and induce the degradation of Her2 tyrosine kinase. Bioorg. Med. Chem. 10, 3555–3564 (2002).

    Article  CAS  PubMed  Google Scholar 

  189. Marcu, M. G., Chadli, A., Bouhouche, I., Catelli, M. & Neckers, L. M. The heat shock protein 90 antagonist novobiocin interacts with a previously unrecognized ATP-binding domain in the carboxyl terminus of the chaperone. J. Biol. Chem. 275, 37181–37186 (2000).

    Article  CAS  PubMed  Google Scholar 

  190. Whitesell, L. & Lindquist, S. L. HSP90 and the chaperoning of cancer. Nat. Rev. Cancer 5, 761–772 (2005).

    Article  CAS  PubMed  Google Scholar 

  191. Garg, G., Khandelwal, A. & Blagg, B. S. Anticancer inhibitors of Hsp90 function: beyond the usual suspects. Adv. Cancer Res. 129, 51–88 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Trepel, J., Mollapour, M., Giaccone, G. & Neckers, L. Targeting the dynamic HSP90 complex in cancer. Nat. Rev. Cancer 10, 537–549 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Caldas-Lopes, E. et al. Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models. Proc. Natl Acad. Sci. USA 106, 8368–8373 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Proia, D. A. et al. HSP90 inhibitor-SN-38 conjugate strategy for targeted delivery of topoisomerase I inhibitor to tumors. Mol. Cancer Ther. 14, 2422–2432 (2015).

    Article  CAS  PubMed  Google Scholar 

  195. Heske, C. M. et al. STA-8666, a novel HSP90 inhibitor/SN-38 drug conjugate, causes complete tumor regression in preclinical mouse models of pediatric sarcoma. Oncotarget 7, 65540–65552 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  196. Pashtan, I., Tsutsumi, S., Wang, S. Q., Xu, W. P. & Neckers, L. Targeting Hsp90 prevents escape of breast cancer cells from tyrosine kinase inhibition. Cell Cycle 7, 2936–2941 (2008).

    Article  CAS  PubMed  Google Scholar 

  197. Smith, D. F. Dynamics of heat shock protein 90-progesterone receptor binding and the disactivation loop model for steroid receptor complexes. Mol. Endocrinol. 7, 1418–1429 (1993).

    CAS  PubMed  Google Scholar 

  198. van Oosten-Hawle, P., Porter, R. S. & Morimoto, R. I. Regulation of organismal proteostasis by transcellular chaperone signaling. Cell 153, 1366–1378 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Grad, I. et al. The Hsp90 cochaperone p23 is essential for perinatal survival. Mol. Cell. Biol. 26, 8976–8983 (2006). Shows in C. elegans that the level of HSP90 in one tissue affects the expression of HSP90 in other tissues in a non-cell-autonomous manner, which reveals a novel transcellular signalling pathway.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Barrott, J. J. & Haystead, T. A. Hsp90, an unlikely ally in the war on cancer. FEBS J. 280, 1381–1396 (2013).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the SFB1035 and IMPRS-LS grants. Furthermore, the authors thank F. Hagn, T. Madl and S. Lagleder for providing access to unpublished structural data. The authors also acknowledge all of the work that could not be cited within the scope of this article.

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Glossary

Chaperones

Proteins that form a complex with protein substrates to influence structural rearrangements, which are required for the activation or folding of the substrate. Chaperones dissociate from their substrates when this process is complete.

Proteostasis

Maintenance of the integrity of the cellular protein network; it is also referred to as protein homeostasis.

Clients

Substrates that physically interact with heat shock protein 90 (HSP90). The activity of clients is influenced by HSP90.

Heat shock response

Regulation of gene expression in response to high temperatures.

Co-chaperones

Non-client proteins that physically interact with a chaperone protein and assist the chaperone in its function to fold or activate other proteins.

HSP70

(Heat shock protein 70). A family of 70 kDa ATP-dependent molecular chaperones with constitutively expressed and stress-induced members. HSP70 proteins bind to linear sequences in unfolded segments of proteins. Several co-chaperones (including ATPase accelerators, nucleotide exchange factors, and so on) regulate its function.

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Schopf, F., Biebl, M. & Buchner, J. The HSP90 chaperone machinery. Nat Rev Mol Cell Biol 18, 345–360 (2017). https://doi.org/10.1038/nrm.2017.20

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