Cell Stress and Chaperones

, Volume 14, Issue 1, pp 83–94 | Cite as

Plasticity of the Hsp90 chaperone machine in divergent eukaryotic organisms

  • Jill L. JohnsonEmail author
  • Celeste Brown
Original Paper


Hsp90 is critical for the regulation and activation of numerous client proteins critical for diverse functions such as cell growth, differentiation, and reproduction. Cytosolic Hsp90 function is dependent on a battery of co-chaperone proteins that regulate the ATPase activity of Hsp90 function or direct Hsp90 to interact with specific client proteins. Little is known about how Hsp90 complexes vary between different organisms and how this affects the scope of clients that are activated by Hsp90. This study determined whether ten distinct Hsp90 co-chaperones were encoded by genes in 19 disparate eukaryotic organisms. Surprisingly, none of the co-chaperones were present in all organisms. The co-chaperone Hop/Sti1 was most widely dispersed (18 out of 19 species), while orthologs of Cdc37, which is critical for the stability and activation of diverse protein kinases in yeast and mammals, were identified in only nine out of 19 species examined. The organism with the smallest proteome, Encephalitozoon cuniculi, contained only three of these co-chaperones, suggesting a correlation between client diversity and the complexity of the Hsp90 co-chaperone machine. Our results suggest co-chaperones are critical for cytosolic Hsp90 function in vivo, but that the composition of Hsp90 complexes varies depending on the specialized protein folding requirements of divergent species.


Aha1 Co-chaperone Tetratricopeptide repeat Immunophilin Hop p23 



heat shock protein


tetratricopeptide repeat


basic local alignment search tool



We thank David Smith, Doug Cole, and Gustavo Arrizabalaga for helpful advice and careful reading of this manuscript. This project was funded in part by the U.S. Department of Agriculture HATCH/CREES IDA01266. This publication was made possible by Grant P20 RR15587 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or NIH.

Supplementary material

12192_2008_58_MOESM1_ESM.doc (8.5 mb)
ESM 1 (DOC 8.53 MB)


  1. Abrahamsen MS, Templeton TJ, Enomoto S, Abrahante JE, Zhu G, Lancto CA, Deng M, Liu C, Widmer G, Tzipori S et al (2004) Complete genome sequence of the apicomplexan, Cryptosporidium parvum. Science 304:441–445 doi: 10.1126/science.1094786 PubMedCrossRefGoogle Scholar
  2. Ali MM, Roe SM, Vaughan CK, Meyer P, Panaretou B, Piper PW, Prodromou C, Pearl LH (2006) Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex. Nature 440:1013–1017 doi: 10.1038/nature04716 PubMedCrossRefGoogle Scholar
  3. Armbrust EV, Berges JA, Bowler C, Green BR, Martinez D, Putnam NH, Zhou S, Allen AE, Apt KE, Bechner M et al (2004) The genome of the diatom Thalassiosira pseudonana: ecology, evolution, and metabolism. Science 306:79–86 doi: 10.1126/science.1101156 PubMedCrossRefGoogle Scholar
  4. Aviezer-Hagai K, Skovorodnikova J, Galigniana M, Farchi-Pisanty O, Maayan E, Bocovza S, Efrat Y, von Koskull-Doring P, Ohad N, Breiman A (2007) Arabidopsis immunophilins ROF1 (AtFKBP62) and ROF2 (AtFKBP65) exhibit tissue specificity, are heat-stress induced, and bind HSP90. Plant Mol Biol 63:237–55 doi: 10.1007/s11103-006-9085-z PubMedCrossRefGoogle Scholar
  5. Barik S (2006) Immunophilins: for the love of proteins. Cell Mol Life Sci 63:2889–900 doi: 10.1007/s00018-006-6215-3 PubMedCrossRefGoogle Scholar
  6. Bhattarai KK, Li Q, Liu Y, Dinesh-Kumar SP, Kaloshian I (2007) The MI-1-mediated pest resistance requires Hsp90 and Sgt1. Plant Physiol 144:312–323 doi: 10.1104/pp.107.097246 PubMedCrossRefGoogle Scholar
  7. Boter M, Amigues B, Peart J, Breuer C, Kadota Y, Casais C, Moore G, Kleanthous C, Ochsenbein F, Shirasu K et al (2007) Structural and functional analysis of SGT1 reveals that its interaction with HSP90 is required for the accumulation of Rx, an R protein involved in plant immunity. Plant Cell 19:3791–804 doi: 10.1105/tpc.107.050427 PubMedCrossRefGoogle Scholar
  8. Boulon S, Marmier-Gourrier N, Pradet-Balade B, Wurth L, Verheggen C, Jady BE, Rothe B, Pescia C, Robert MC, Kiss T et al (2008) The Hsp90 chaperone controls the biogenesis of L7Ae RNPs through conserved machinery. J Cell Biol 180:579–95 doi: 10.1083/jcb.200708110 PubMedCrossRefGoogle Scholar
  9. Caplan AJ, Mandal AK, Theodoraki MA (2007) Molecular chaperones and protein kinase quality control. Trends Cell Biol 17:87–92 doi: 10.1016/j.tcb.2006.12.002 PubMedCrossRefGoogle Scholar
  10. Carrigan PE, Riggs DL, Chinkers M, Smith DF (2005) Functional comparison of human and Drosophila Hop reveals novel role in steroid receptor maturation. J Biol Chem 280:8906–8911 doi: 10.1074/jbc.M414245200 PubMedCrossRefGoogle Scholar
  11. Catlett MG, Kaplan KB (2006) Sgt1p is a unique co-chaperone that acts as a client-adaptor to link Hsp90 to Skp1p. J Biol Chem 281:33739–33748 doi: 10.1074/jbc.M603847200 PubMedCrossRefGoogle Scholar
  12. Chadli A, Graham JD, Abel MG, Jackson TA, Gordon DF, Wood WM, Felts SJ, Horwitz KB, Toft D (2006) GCUNC-45 is a novel regulator for the progesterone receptor/hsp90 chaperoning pathway. Mol Cell Biol 26:1722–1730 doi: 10.1128/MCB.26.5.1722-1730.2006 PubMedCrossRefGoogle Scholar
  13. Chen B, Zhong D, Monteiro A (2006) Comparative genomics and evolution of the HSP90 family of genes across all kingdoms of organisms. BMC Genomics 7:156 doi: 10.1186/1471-2164-7-156 PubMedCrossRefGoogle Scholar
  14. Cox MB, Riggs DL, Hessling M, Schumacher F, Buchner J, Smith DF (2007) Fkbp52 phosphorylation: a potential mechanism for regulating steroid hormone receptor activity. Mol Endocrinol 21:2956–2967 doi: 10.1210/me.2006-0547 PubMedCrossRefGoogle Scholar
  15. Crevel G, Bates H, Huikeshoven H, Cotterill S (2001) The Drosophila Dpit47 protein is a nuclear Hsp90 co-chaperone that interacts with DNA polymerase alpha. J Cell Sci 114:2015–2025PubMedGoogle Scholar
  16. Crevel G, Bennett D, Cotterill S (2008) The human TPR protein TTC4 is a putative Hsp90 co-chaperone which interacts with CDC6 and shows alterations in transformed cells. PLoS ONE 3:e0001737 doi: 10.1371/journal.pone.0001737
  17. de la Fuente van Bentem S, Vossen JH, de Vries KJ, van Wees S, Tameling WI, Dekker HL, de Koster CG, Haring MA, Takken FL, Cornelissen BJ (2005) Heat shock protein 90 and its co-chaperone protein phosphatase 5 interact with distinct regions of the tomato I-2 disease resistance protein. Plant J 43:284–98 doi: 10.1111/j.1365-313X.2005.02450.x PubMedCrossRefGoogle Scholar
  18. Eisen JA, Coyne RS, Wu M, Wu D, Thiagarajan M, Wortman JR, Badger JH, Ren Q, Amedeo P, Jones KM (2006) Macronuclear genome sequence of the ciliate Tetrahymena thermophila, a model eukaryote. PLoS Biol 4:e286 doi: 10.1371/journal.pbio.0040286 PubMedCrossRefGoogle Scholar
  19. Felsenstein J (2005) PHYLIP (Phylogeny Inference Package) version 3$6$ Distributed by the author. Department of Genome Sciences, University of Washington, SeattleGoogle Scholar
  20. Felts SJ, Karnitz LM, Toft DO (2007) Functioning of the Hsp90 machine in chaperoning checkpoint kinase I (Chk1) and the progesterone receptor (PR). Cell Stress Chaperones 12:353–363 doi: 10.1379/CSC-299.1 PubMedCrossRefGoogle Scholar
  21. Felts SJ, Owen BA, Nguyen P, Trepel J, Donner DB, Toft DO (2000) The hsp90-related protein TRAP1 is a mitochondrial protein with distinct functional properties. J Biol Chem 275:3305–3312 doi: 10.1074/jbc.275.5.3305 PubMedCrossRefGoogle Scholar
  22. Flom G, Behal RH, Rosen L, Cole DG, Johnson JL (2007) Definition of the minimal fragments of Sti1 required for dimerization, interaction with Hsp70 and Hsp90 and in vivo functions. Biochem J 404:159–167 doi: 10.1042/BJ20070084 PubMedCrossRefGoogle Scholar
  23. Golden T, Swingle M, Honkanen RE (2008) The role of serine/threonine protein phosphatase type 5 (PP5) in the regulation of stress-induced signaling networks and cancer. Cancer Metastasis Rev 27:169–178 doi: 10.1007/s10555-008-9125-z PubMedCrossRefGoogle Scholar
  24. Grad I, McKee TA, Ludwig SM, Hoyle GW, Ruiz P, Wurst W, Floss T, Miller CA 3rd, Picard D (2006) The Hsp90 cochaperone p23 is essential for perinatal survival. Mol Cell Biol 26:8976–8983 doi: 10.1128/MCB.00734-06 PubMedCrossRefGoogle Scholar
  25. Hainzl O, Wegele H, Richter K, Buchner J (2004) Cns1 is an activator of the Ssa1 ATPase activity. J Biol Chem 279:23267–23273 doi: 10.1074/jbc.M402189200 PubMedCrossRefGoogle Scholar
  26. Harst A, Lin H, Obermann WM (2005) Aha1 competes with Hop, p50 and p23 for binding to the molecular chaperone Hsp90 and contributes to kinase and hormone receptor activation. Biochem J 387:789–796 doi: 10.1042/BJ20041283 PubMedCrossRefGoogle Scholar
  27. Hinds TD Jr, Sanchez ER (2007) Protein phosphatase 5. Int J Biochem Cell Biol. PMID: 17951098.Google Scholar
  28. Holt SE, Aisner DL, Baur J, Tesmer VM, Dy M, Ouellette M, Trager JB, Morin GB, Toft DO, Shay JW (1999) Functional requirement of p23 and Hsp90 in telomerase complexes. Genes Dev 13:817–26 doi: 10.1101/gad.13.7.817 PubMedCrossRefGoogle Scholar
  29. Jones C, Anderson S, Singha UK, Chaudhuri M (2008) Protein phosphatase 5 is required for Hsp90 function during proteotoxic stresses in Trypanosoma brucei. Parasitol Res 102:835–844 doi: 10.1007/s00436-007-0817-z PubMedCrossRefGoogle Scholar
  30. Kamal A, Thao L, Sensintaffar J, Zhang L, Boehm MF, Fritz LC, Burrows FJ (2003) A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425:407–410 doi: 10.1038/nature01913 PubMedCrossRefGoogle Scholar
  31. Kang BH, Plescia J, Dohi T, Rosa J, Doxsey SJ, Altieri DC (2007) Regulation of tumor cell mitochondrial homeostasis by an organelle-specific Hsp90 chaperone network. Cell 131:257–270 doi: 10.1016/j.cell.2007.08.028 PubMedCrossRefGoogle Scholar
  32. Katinka MD, Duprat S, Cornillot E, Metenier G, Thomarat F, Prensier G, Barbe V, Peyretaillade E, Brottier P, Wincker P et al (2001) Genome sequence and gene compaction of the eukaryote parasite Encephalitozoon cuniculi. Nature 414:450–453 doi: 10.1038/35106579 PubMedCrossRefGoogle Scholar
  33. Lee P, Shabbir A, Cardozo C, Caplan AJ (2004) Sti1 and Cdc37 can stabilize Hsp90 in chaperone complexes with a protein kinase. Mol Biol Cell 15:1785–1792 doi: 10.1091/mbc.E03-07-0480 PubMedCrossRefGoogle Scholar
  34. Mandal AK, Lee P, Chen JA, Nillegoda N, Heller A, DiStasio S, Oen H, Victor J, Nair DM, Brodsky JL (2007) Cdc37 has distinct roles in protein kinase quality control that protect nascent chains from degradation and promote posttranslational maturation. J Cell Biol 176:319–328 doi: 10.1083/jcb.200604106 PubMedCrossRefGoogle Scholar
  35. Mayor A, Martinon F, De Smedt T, Petrilli V, Tschopp J (2007) A crucial function of SGT1 and HSP90 in inflammasome activity links mammalian and plant innate immune responses. Nat Immunol 8:497–503 doi: 10.1038/ni1459 PubMedCrossRefGoogle Scholar
  36. Mayr C, Richter K, Lilie H, Buchner J (2000) Cpr6 and Cpr7, two closely related Hsp90-associated immunophilins from Saccharomyces cerevisiae, differ in their functional properties. J Biol Chem 275:34140–6 doi: 10.1074/jbc.M005251200 PubMedCrossRefGoogle Scholar
  37. McClellan AJ, Xia Y, Deutschbauer AM, Davis RW, Gerstein M, Frydman J (2007) Diverse cellular functions of the hsp90 molecular chaperone uncovered using systems approaches. Cell 131:121–35 doi: 10.1016/j.cell.2007.07.036 PubMedCrossRefGoogle Scholar
  38. Merchant SS, Prochnik SE, Vallon O, Harris EH, Karpowicz SJ, Witman GB, Terry A, Salamov A, Fritz-Laylin LK, Marechal-Drouard L et al (2007) The Chlamydomonas genome reveals the evolution of key animal and plant functions. Science 318:245–250 doi: 10.1126/science.1143609 PubMedCrossRefGoogle Scholar
  39. Meyer P, Prodromou C, Liao C, Hu B, Mark Roe S, Vaughan CK, Vlasic I, Panaretou B, Piper PW, Pearl LH (2004) Structural basis for recruitment of the ATPase activator Aha1 to the Hsp90 chaperone machinery. Embo J 23:511–519 doi: 10.1038/sj.emboj.7600060 PubMedCrossRefGoogle Scholar
  40. Miyagawa Y, Lee JM, Maeda T, Koga K, Kawaguchi Y, Kusakabe T (2005) Differential expression of a Bombyx mori AHA1 homologue during spermatogenesis. Insect Mol Biol 14:245–253 doi: 10.1111/j.1365-2583.2005.00553.x PubMedCrossRefGoogle Scholar
  41. Morrison HG, McArthur AG, Gillin FD, Aley SB, Adam RD, Olsen GJ, Best AA, Cande WZ, Chen F, Cipriano MJ et al (2007) Genomic minimalism in the early diverging intestinal parasite Giardia lamblia. Science 317:1921–1926 doi: 10.1126/science.1143837 PubMedCrossRefGoogle Scholar
  42. Munoz MJ, Bejarano ER, Daga RR, Jimenez J (1999) The identification of Wos2, a p23 homologue that interacts with Wee1 and Cdc2 in the mitotic control of fission yeasts. Genetics 153:1561–1572PubMedGoogle Scholar
  43. Nathan DF, Vos MH, Lindquist S (1999) Identification of SSF1, CNS1, and HCH1 as multicopy suppressors of a Saccharomyces cerevisiae Hsp90 loss-of-function mutation. Proc Natl Acad Sci USA 96:1409–1414 doi: 10.1073/pnas.96.4.1409 PubMedCrossRefGoogle Scholar
  44. Pain A, Renauld H, Berriman M, Murphy L, Yeats CA, Weir W, Kerhornou A, Aslett M, Bishop R, Bouchier C et al (2005) Genome of the host-cell transforming parasite Theileria annulata compared with T. parva. Science 309:131–133 doi: 10.1126/science.1110418 PubMedCrossRefGoogle Scholar
  45. Panaretou B, Siligardi G, Meyer P, Maloney A, Sullivan JK, Singh S, Millson SH, Clarke PA, Naaby-Hansen S, Stein R et al (2002) Activation of the ATPase activity of hsp90 by the stress-regulated cochaperone aha1. Mol Cell 10:1307–1318 doi: 10.1016/S1097-2765(02)00785-2 PubMedCrossRefGoogle Scholar
  46. Pearl LH, Prodromou C (2006) Structure and mechanism of the hsp90 molecular chaperone machinery. Annu Rev Biochem 75:271–94 doi: 10.1146/annurev.biochem.75.103004.142738 PubMedCrossRefGoogle Scholar
  47. Poetsch M, Dittberner T, Cowell JK, Woenckhaus C (2000) TTC4, a novel candidate tumor suppressor gene at 1p31 is often mutated in malignant melanoma of the skin. Oncogene 19:5817–5820 doi: 10.1038/sj.onc.1203961 PubMedCrossRefGoogle Scholar
  48. Pratt WB, Galigniana MD, Harrell JM, DeFranco DB (2004) Role of hsp90 and the hsp90-binding immunophilins in signalling protein movement. Cell Signal 16:857–872 doi: 10.1016/j.cellsig.2004.02.004 PubMedCrossRefGoogle Scholar
  49. Richardson JM, Dornan J, Opamawutthikul M, Bruce S, Page AP, Walkinshaw MD (2007) Cloning, expression and characterisation of FKB-6, the sole large TPR-containing immunophilin from C. elegans. Biochem Biophys Res Commun 360:566–572 doi: 10.1016/j.bbrc.2007.06.080 PubMedCrossRefGoogle Scholar
  50. Richter K, Buchner J (2006) hsp90: twist and fold. Cell 127:251–253 doi: 10.1016/j.cell.2006.10.004 PubMedCrossRefGoogle Scholar
  51. Richter K, Reinstein J, Buchner J (2007) A Grp on the Hsp90 mechanism. Mol Cell 28:177–179 doi: 10.1016/j.molcel.2007.10.007 PubMedCrossRefGoogle Scholar
  52. Riggs D, Cox M, Cheung-Flynn J, Prapapanich V, Carrigan P, Smith D (2004) Functional specificity of co-chaperone interactions with Hsp90 client proteins. Crit Rev Biochem Mol Biol 39:279–295 doi: 10.1080/10409230490892513 PubMedCrossRefGoogle Scholar
  53. Roe SM, Ali MM, Meyer P, Vaughan CK, Panaretou B, Piper PW, Prodromou C, Pearl LH (2004) The Mechanism of Hsp90 regulation by the protein kinase-specific cochaperone p50(cdc37). Cell 116:87–98 doi: 10.1016/S0092-8674(03)01027-4 PubMedCrossRefGoogle Scholar
  54. Scheufler C, Brinker A, Bourenkov G, Pegoraro S, Moroder L, Bartunik H, Hartl FU, Moarefi I (2000) Structure of TPR domain-peptide complexes: critical elements in the assembly of the Hsp70-Hsp90 multichaperone machine. Cell 101:199–210 doi: 10.1016/S0092-8674(00)80830-2 PubMedCrossRefGoogle Scholar
  55. Smith DF, Toft DO (2008) The intersection of steroid receptors with molecular chaperones: observations and questions. Mol Endocrinol. PMID: 18451092.Google Scholar
  56. Tesic M, Marsh JA, Cullinan SB, Gaber RF (2003) Functional interactions between Hsp90 and the Co-chaperones Cns1 and Cpr7 in Saccharomyces cerevisiae. J Biol Chem 278:32692–326701 doi: 10.1074/jbc.M304315200 PubMedCrossRefGoogle Scholar
  57. Toogun OA, Zeiger W, Freeman BC (2007) The p23 molecular chaperone promotes functional telomerase complexes through DNA dissociation. Proc Natl Acad Sci USA 104:5765–5770 doi: 10.1073/pnas.0701442104 PubMedCrossRefGoogle Scholar
  58. Travers SA, Fares MA (2007) Functional coevolutionary networks of the Hsp70–Hop–Hsp90 system revealed through computational analyses. Mol Biol Evol 24:1032–1044 doi: 10.1093/molbev/msm022 PubMedCrossRefGoogle Scholar
  59. Wandinger SK, Suhre MH, Wegele H, Buchner J (2006) The phosphatase Ppt1 is a dedicated regulator of the molecular chaperone Hsp90. Embo J 25:367–376 doi: 10.1038/sj.emboj.7600930 PubMedCrossRefGoogle Scholar
  60. Wang X, Venable J, LaPointe P, Hutt DM, Koulov AV, Coppinger J, Gurkan C, Kellner W, Matteson J, Plutner H et al (2006) Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell 127:803–815 doi: 10.1016/j.cell.2006.09.043 PubMedCrossRefGoogle Scholar
  61. Wegele H, Muller L, Buchner J (2004) Hsp70 and Hsp90—a relay team for protein folding. Rev Physiol Biochem Pharmacol 151:1–44 doi: 10.1007/s10254-003-0021-1 PubMedCrossRefGoogle Scholar
  62. Wegele H, Wandinger SK, Schmid AB, Reinstein J, Buchner J (2006) Substrate transfer from the chaperone Hsp70 to Hsp90. J Mol Biol 356:802–811 doi: 10.1016/j.jmb.2005.12.008 PubMedCrossRefGoogle Scholar
  63. Whitesell L, Lindquist SL (2005) HSP90 and the chaperoning of cancer. Nat Rev Cancer 5:761–772 doi: 10.1038/nrc1716 PubMedCrossRefGoogle Scholar
  64. Wickstead B, Gull K (2006) A “holistic” kinesin phylogeny reveals new kinesin families and predicts protein functions. Mol Biol Cell 17:1734–1743 doi: 10.1091/mbc.E05-11-1090 PubMedCrossRefGoogle Scholar
  65. Young JC, Obermann WM, Hartl FU (1998) Specific binding of tetratricopeptide repeat proteins to the C-terminal 12-kDa domain of hsp90. J Biol Chem 273:18007–18010. doi: 10.1074/jbc.273.29.18007 PubMedCrossRefGoogle Scholar
  66. Zhao R, Davey M, Hsu YC, Kaplanek P, Tong A, Parsons AB, Krogan N, Cagney G, Mai D, Greenblatt J et al (2005) Navigating the chaperone network: an integrative map of physical and genetic interactions mediated by the hsp90 chaperone. Cell 120:715–727. doi: 10.1016/j.cell.2004.12.024 PubMedCrossRefGoogle Scholar
  67. Zhao R, Kakihara Y, Gribun A, Huen J, Yang G, Khanna M, Costanzo M, Brost RL, Boone C, Hughes TR et al (2008) Molecular chaperone Hsp90 stabilizes Pih1/Nop17 to maintain R2TP complex activity that regulates snoRNA accumulation. J Cell Biol 180:563–578. doi: 10.1083/jcb.200709061 PubMedCrossRefGoogle Scholar

Copyright information

© Cell Stress Society International 2008

Authors and Affiliations

  1. 1.Department of MicrobiologyMolecular Biology and Biochemistry and the Center for Reproductive BiologyMoscowUSA
  2. 2.Department of Biological SciencesUniversity of IdahoMoscowUSA
  3. 3.LSS 142 Department of Microbiology, Molecular Biology and BiochemistryUniversity of IdahoMoscowUSA

Personalised recommendations