Skip to main content
SpringerLink
Log in

Human Hsp90 cochaperones: perspectives on tissue-specific expression and identification of cochaperones with similar in vivo functions

  • Perspective and Reflection Article
  • Published:
Cell Stress and Chaperones Aims and scope

Abstract

The Hsp90 molecular chaperone is required for the function of hundreds of different cellular proteins. Hsp90 and a cohort of interacting proteins called cochaperones interact with clients in an ATP-dependent cycle. Cochaperone functions include targeting clients to Hsp90, regulating Hsp90 ATPase activity, and/or promoting Hsp90 conformational changes as it progresses through the cycle. Over the last 20 years, the list of cochaperones identified in human cells has grown from the initial six identified in complex with steroid hormone receptors and protein kinases to about fifty different cochaperones found in Hsp90-client complexes. These cochaperones may be placed into three groups based on shared Hsp90 interaction domains. Available evidence indicates that cochaperones vary in client specificity, abundance, and tissue distribution. Many of the cochaperones have critical roles in regulation of cancer and neurodegeneration. A more limited set of cochaperones have cellular functions that may be limited to tissues such as muscle and testis. It is likely that a small set of cochaperones are part of the core Hsp90 machinery required for the folding of a wide range of clients. The presence of more selective cochaperones may allow greater control of Hsp90 activities across different tissues or during development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

Not applicable.

References

  • Alekseev OM, Widgren EE, Richardson RT, O'Rand MG (2005) Association of NASP with HSP90 in mouse spermatogenic cells: stimulation of ATPase activity and transport of linker histones into nuclei. J Biol Chem 280:2904–2911

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Assimon VA, Southworth DR, Gestwicki JE (2015) Specific binding of tetratricopeptide repeat proteins to heat shock protein 70 (Hsp70) and heat shock protein 90 (Hsp90) is regulated by affinity and phosphorylation. Biochemistry 54:7120–7131

    Article  CAS  PubMed  Google Scholar 

  • Benson DR, Lovell S, Mehzabeen N, Galeva N, Cooper A, Gao P, Battaile KP, Zhu H (2019) Crystal structures of the naturally fused CS and cytochrome b5 reductase (b5R) domains of Ncb5or reveal an expanded CS fold, extensive CS-b5R interactions and productive binding of the NAD(P)(+) nicotinamide ring. Acta Crystallogr D Struct Biol 75:628–638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Biebl MM, Riedl M, Buchner J (2020) Hsp90 Co-chaperones form plastic genetic networks adapted to client maturation. Cell Rep 32:108063

    Article  CAS  PubMed  Google Scholar 

  • Blundell KL, Pal M, Roe SM, Pearl LH, Prodromou C (2017) The structure of FKBP38 in complex with the MEEVD tetratricopeptide binding-motif of Hsp90. PLoS One 12:e0173543

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bohush A, Bieganowski P, Filipek A (2019) Hsp90 and its co-chaperones in neurodegenerative diseases. Int J Mol Sci 20

  • Boitet ER, Reish NJ, Hubbard MG, Gross AK (2019) NudC regulates photoreceptor disk morphogenesis and rhodopsin localization. FASEB J 33:8799–8808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Borkovich KA, Farrelly FW, Finkelstein DB, Taulien J, Lindquist S (1989) hsp82 is an essential protein that is required in higher concentrations for growth of cells at higher temperatures. Mol Cell Biol 9:3919–3930

    CAS  PubMed  PubMed Central  Google Scholar 

  • Brehme M, Voisine C, Rolland T, Wachi S, Soper JH, Zhu Y, Orton K, Villella A, Garza D, Vidal M, Ge H, Morimoto RI (2014) A chaperome subnetwork safeguards proteostasis in aging and neurodegenerative disease. Cell Rep 9:1135–1150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buchanan G, Ricciardelli C, Harris JM, Prescott J, Yu ZC, Jia L, Butler LM, Marshall VR, Scher HI, Gerald WL et al (2007) Control of androgen receptor signaling in prostate cancer by the cochaperone small glutamine rich tetratricopeptide repeat containing protein alpha. Cancer Res 67:10087–10096

    Article  CAS  PubMed  Google Scholar 

  • Calderwood SK (2013) Molecular cochaperones: tumor growth and cancer treatment. Scientifica (Cairo) 2013:217513

    Google Scholar 

  • Calderwood SK, Gong J (2016) Heat shock proteins promote cancer: it's a protection racket. Trends Biochem Sci 41:311–323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Calderwood SK, Murshid A (2017) Molecular chaperone accumulation in cancer and decrease in Alzheimer's disease: the potential roles of HSF1. Frontiers in Neuroscience 11:192

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chadli A, Felts SJ, Toft DO (2008) GCUNC45 is the first Hsp90 co-chaperone to show alpha/beta isoform specificity. J Biol Chem 283:9509–9512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen Y, Zhao M, Wang S, Chen J, Wang Y, Cao Q, Zhou W, Liu J, Xu Z, Tong G, Li J (2009) A novel role for DYX1C1, a chaperone protein for both Hsp70 and Hsp90, in breast cancer. J Cancer Res Clin Oncol 135:1265–1276

    Article  CAS  PubMed  Google Scholar 

  • Cheung-Flynn J, Prapapanich V, Cox MB, Riggs DL, Suarez-Quian C, Smith DF (2005) Physiological role for the cochaperone FKBP52 in androgen receptor signaling. Mol Endocrinol 19:1654–1666

    Article  CAS  PubMed  Google Scholar 

  • Connell P, Ballinger CA, Jiang J, Wu Y, Thompson LJ, Hohfeld J, Patterson C (2001) The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins. Nat Cell Biol 3:93–96

    Article  CAS  PubMed  Google Scholar 

  • Courilleau D, Chastre E, Sabbah M, Redeuilh G, Atfi A, Mester J (2000) B-ind1, a novel mediator of Rac1 signaling cloned from sodium butyrate-treated fibroblasts. J Biol Chem 275:17344–17348

    Article  CAS  PubMed  Google Scholar 

  • Coyne ES, Bedard N, Wykes L, Stretch C, Jammoul S, Li S, Zhang K, Sladek RS, Bathe OF, Jagoe RT, Posner BI, Wing SS (2018) Knockout of USP19 deubiquitinating enzyme prevents muscle wasting by modulating insulin and glucocorticoid signaling. Endocrinology 159:2966–2977

    Article  CAS  PubMed  Google Scholar 

  • Crackower MA, Kolas NK, Noguchi J, Sarao R, Kikuchi K, Kaneko H, Kobayashi E, Kawai Y, Kozieradzki I, Landers R, Mo R, Hui CC, Nieves E, Cohen PE, Osborne LR, Wada T, Kunieda T, Moens PB, Penninger JM (2003) Essential role of Fkbp6 in male fertility and homologous chromosome pairing in meiosis. Science 300:1291–1295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • D'Andrea LD, Regan L (2003) TPR proteins: the versatile helix. Trends Biochem Sci 28:655–662

    Article  CAS  PubMed  Google Scholar 

  • De Leon JT, Iwai A, Feau C, Garcia Y, Balsiger HA, Storer CL, Suro RM, Garza KM, Lee S, Kim YS et al (2011) Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells. Proc Natl Acad Sci U S A 108:11878–11883

    Article  PubMed  PubMed Central  Google Scholar 

  • Dong F, Shinohara K, Botilde Y, Nabeshima R, Asai Y, Fukumoto A, Hasegawa T, Matsuo M, Takeda H, Shiratori H, Nakamura T, Hamada H (2014) Pih1d3 is required for cytoplasmic preassembly of axonemal dynein in mouse sperm. J Cell Biol 204:203–213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dunn DM, Woodford MR, Truman AW, Jensen SM, Schulman J, Caza T, Remillard TC, Loiselle D, Wolfgeher D, Blagg BS et al (2015) c-Abl mediated tyrosine phosphorylation of Aha1 activates its co-chaperone function in cancer cells. Cell Rep 12:1006–1018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Echeverria PC, Briand PA, Picard D (2016) A remodeled Hsp90 molecular chaperone ensemble with the novel cochaperone Aarsd1 is required for muscle differentiation. Mol Cell Biol 36:1310–1321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Echtenkamp FJ, Zelin E, Oxelmark E, Woo JI, Andrews BJ, Garabedian M, Freeman BC (2011) Global functional map of the p23 molecular chaperone reveals an extensive cellular network. Mol Cell 43:229–241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Echtenkamp FJ, Gvozdenov Z, Adkins NL, Zhang Y, Lynch-Day M, Watanabe S, Peterson CL, Freeman BC (2016) Hsp90 and p23 molecular chaperones control chromatin architecture by maintaining the functional pool of the RSC chromatin remodeler. Mol Cell 64:888–899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Erlejman AG, Lagadari M, Harris DC, Cox MB, Galigniana MD (2014) Molecular chaperone activity and biological regulatory actions of the TPR-domain immunophilins FKBP51 and FKBP52. Curr Protein Pept Sci 15:205–215

    Article  CAS  PubMed  Google Scholar 

  • Fabczak H, Osinka A (2019) Role of the novel Hsp90 co-chaperones in Dynein Arms' Preassembly. Int J Mol Sci 20

  • Ferretti R, Palumbo V, Di Savino A, Velasco S, Sbroggio M, Sportoletti P, Micale L, Turco E, Silengo L, Palumbo G et al (2010) Morgana/chp-1, a ROCK inhibitor involved in centrosome duplication and tumorigenesis. Dev Cell 18:486–495

    Article  CAS  PubMed  Google Scholar 

  • Ferretti R, Sbroggio M, Di Savino A, Fusella F, Bertero A, Michowski W, Tarone G, Brancaccio M (2011) Morgana and melusin: two fairies chaperoning signal transduction. Cell Cycle 10:3678–3683

    Article  CAS  PubMed  Google Scholar 

  • Forafonov F, Toogun OA, Grad I, Suslova E, Freeman BC, Picard D (2008) p23/Sba1p protects against Hsp90 inhibitors independently of its intrinsic chaperone activity. Mol Cell Biol 28:3446–3456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Freeman BC, Yamamoto KR (2002) Disassembly of transcriptional regulatory complexes by molecular chaperones. Science 296:2232–2235

    Article  CAS  PubMed  Google Scholar 

  • Freeman BC, Toft DO, Morimoto RI (1996) Molecular chaperone machines: chaperone activities of the cyclophilin Cyp-40 and the steroid aporeceptor-associated protein p23. Science 274:1718–1720

    Article  CAS  PubMed  Google Scholar 

  • Fu Q, Wang W, Zhou T, Yang Y (2016) Emerging roles of NudC family: from molecular regulation to clinical implications. Sci China Life Sci 59:455–462

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Ranea JA, Mirey G, Camonis J, Valencia A (2002) p23 and HSP20/alpha-crystallin proteins define a conserved sequence domain present in other eukaryotic protein families. FEBS Lett 529:162–167

    Article  CAS  PubMed  Google Scholar 

  • Ghosh A, Dai Y, Biswas P, Stuehr DJ (2019) Myoglobin maturation is driven by the hsp90 chaperone machinery and by soluble guanylyl cyclase. FASEB J 33:9885–9896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goral A, Bieganowski P, Prus W, Krzemien-Ojak L, Kadziolka B, Fabczak H, Filipek A (2016) Calcyclin binding protein/Siah-1 interacting protein is a Hsp90 binding chaperone. PLoS One 11:e0156507

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Grad I, Cederroth CR, Walicki J, Grey C, Barluenga S, Winssinger N, De Massy B, Nef S, Picard D (2010) The molecular chaperone Hsp90alpha is required for meiotic progression of spermatocytes beyond pachytene in the mouse. PLoS One 5:e15770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guy NC, Garcia YA, Sivils JC, Galigniana MD, Cox MB (2015) Functions of the Hsp90-binding FKBP immunophilins. Subcell Biochem 78:35–68

    Article  CAS  PubMed  Google Scholar 

  • Han B, Zhang YY, Xu K, Bai Y, Wan LH, Miao SK, Zhang KX, Zhang HW, Liu Y, Zhou LM (2018) NUDCD1 promotes metastasis through inducing EMT and inhibiting apoptosis in colorectal cancer. Am J Cancer Res 8:810–823

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hatakeyama S, Matsumoto M, Yada M, Nakayama KI (2004) Interaction of U-box-type ubiquitin-protein ligases (E3s) with molecular chaperones. Genes Cells 9:533–548

    Article  CAS  PubMed  Google Scholar 

  • He WT, Zheng XM, Zhang YH, Gao YG, Song AX, van der Goot FG, Hu HY (2016) Cytoplasmic ubiquitin-specific protease 19 (USP19) modulates aggregation of polyglutamine-expanded Ataxin-3 and Huntingtin through the HSP90 chaperone. PLoS One 11:e0147515

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • He H, Dai J, Wang X, Qian X, Zhao J, Wang H, Xu D (2018) NudCD1 affects renal cell carcinoma through regulating LIS1/Dynein signaling pathway. Am J Transl Res 10:519–524

    CAS  PubMed  PubMed Central  Google Scholar 

  • Herold C, Hooli BV, Mullin K, Liu T, Roehr JT, Mattheisen M, Parrado AR, Bertram L, Lange C, Tanzi RE (2016) Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3. Mol Psychiatry 21:1608–1612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hidalgo-de-Quintana J, Evans RJ, Cheetham ME, van der Spuy J (2008) The Leber congenital amaurosis protein AIPL1 functions as part of a chaperone heterocomplex. Invest Ophthalmol Vis Sci 49:2878–2887

    Article  PubMed  Google Scholar 

  • Howell M, Brickner H, Delorme-Walker VD, Choi J, Saffin JM, Miller D, Panopoulos A, DerMardirossian C, Fotedar A, Margolis RL, Fotedar R (2015) WISp39 binds phosphorylated Coronin 1B to regulate Arp2/3 localization and Cofilin-dependent motility. J Cell Biol 208:961–974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang H, Luo B, Wang B, Wu Q, Liang Y, He Y (2018) Identification of potential gene interactions in heart failure caused by idiopathic dilated cardiomyopathy. Med Sci Monit 24:7697–7709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ichiyanagi T, Ichiyanagi K, Ogawa A, Kuramochi-Miyagawa S, Nakano T, Chuma S, Sasaki H, Udono H (2014) HSP90alpha plays an important role in piRNA biogenesis and retrotransposon repression in mouse. Nucleic Acids Res 42:11903–11911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jarczowski F, Jahreis G, Erdmann F, Schierhorn A, Fischer G, Edlich F (2009) FKBP36 is an inherent multifunctional glyceraldehyde-3-phosphate dehydrogenase inhibitor. J Biol Chem 284:766–773

    Article  CAS  PubMed  Google Scholar 

  • Jascur T, Brickner H, Salles-Passador I, Barbier V, El Khissiin A, Smith B, Fotedar R, Fotedar A (2005) Regulation of p21(WAF1/CIP1) stability by WISp39, a Hsp90 binding TPR protein. Mol Cell 17:237–249

    Article  CAS  PubMed  Google Scholar 

  • Jha KN, Coleman AR, Wong L, Salicioni AM, Howcroft E, Johnson GR (2013) Heat shock protein 90 functions to stabilize and activate the testis-specific serine/threonine kinases, a family of kinases essential for male fertility. J Biol Chem 288:16308–16320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson JL, Brown C (2009) Plasticity of the Hsp90 chaperone machine in divergent eukaryotic organisms. Cell Stress & Chaperones 14:83–94

    Article  CAS  Google Scholar 

  • Johnson JL, Beito TG, Krco CJ, Toft DO (1994) Characterization of a novel 23-kilodalton protein of unactive progesterone receptor complexes. Mol Cell Biol 14:1956–1963

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kapustian LL, Vigontina OA, Rozhko OT, Ryabenko DV, Michowski W, Lesniak W, Filipek A, Kroupskaya IV, Sidorik LL (2013) Hsp90 and its co-chaperone, Sgt1, as autoantigens in dilated cardiomyopathy. Heart Vessels 28:114–119

    Article  PubMed  Google Scholar 

  • Kirschke E, Goswami D, Southworth D, Griffin PR, Agard DA (2014) Glucocorticoid receptor function regulated by coordinated action of the Hsp90 and Hsp70 chaperone cycles. Cell 157:1685–1697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krzemien-Ojak L, Goral A, Joachimiak E, Filipek A, Fabczak H (2017) Interaction of a novel chaperone PhLP2A with the heat shock protein Hsp90. J Cell Biochem 118:420–429

    Article  CAS  PubMed  Google Scholar 

  • Kwan DH, Yung LY, Ye RD, Wong YH (2012) Activation of Ras-dependent signaling pathways by G(14) -coupled receptors requires the adaptor protein TPR1. J Cell Biochem 113:3486–3497

    Article  CAS  PubMed  Google Scholar 

  • Lackie RE, Maciejewski A, Ostapchenko VG, Marques-Lopes J, Choy WY, Duennwald ML, Prado VF, Prado MAM (2017) The Hsp70/Hsp90 chaperone machinery in neurodegenerative diseases. Frontiers in Neuroscience 11:254

    Article  PubMed  PubMed Central  Google Scholar 

  • LaPointe P, Mercier R, Wolmarans A (2020) Aha-type co-chaperones: the alpha or the omega of the Hsp90 ATPase cycle? Biol Chem 401:423–434

    Article  CAS  PubMed  Google Scholar 

  • Lin W, Zhou X, Zhang M, Li Y, Miao S, Wang L, Zong S, Koide SS (2001) Expression and function of the HSD-3.8 gene encoding a testis-specific protein. Mol Hum Reprod 7:811–818

    Article  CAS  PubMed  Google Scholar 

  • Lorenz OR, Freiburger L, Rutz DA, Krause M, Zierer BK, Alvira S, Cuellar J, Valpuesta JM, Madl T, Sattler M et al (2014) Modulation of the hsp90 chaperone cycle by a stringent client protein. Mol Cell 53:941–953

    Article  CAS  PubMed  Google Scholar 

  • Madeira F, Park YM, Lee J, Buso N, Gur T, Madhusoodanan N, Basutkar P, Tivey ARN, Potter SC, Finn RD, Lopez R (2019) The EMBL-EBI search and sequence analysis tools APIs in 2019. Nucleic Acids Res 47:W636–W641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McDowell CL, Bryan Sutton R, Obermann WM (2009) Expression of Hsp90 chaperome proteins in human tumor tissue. Int J Biol Macromol 45:310–314

    Article  CAS  PubMed  Google Scholar 

  • McLaughlin SH, Sobott F, Yao ZP, Zhang W, Nielsen PR, Grossmann JG, Laue ED, Robinson CV, Jackson SE (2006) The co-chaperone p23 arrests the Hsp90 ATPase cycle to trap client proteins. J Mol Biol 356:746–758

    Article  CAS  PubMed  Google Scholar 

  • Moffatt NS, Bruinsma E, Uhl C, Obermann WM, Toft D (2008) Role of the cochaperone Tpr2 in Hsp90 chaperoning. Biochemistry 47:8203–8213

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Morgan RM, Hernandez-Ramirez LC, Trivellin G, Zhou L, Roe SM, Korbonits M, Prodromou C (2012) Structure of the TPR domain of AIP: lack of client protein interaction with the C-terminal alpha-7 helix of the TPR domain of AIP is sufficient for pituitary adenoma predisposition. PLoS One 7:e53339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Most P, Bernotat J, Ehlermann P, Pleger ST, Reppel M, Borries M, Niroomand F, Pieske B, Janssen PM, Eschenhagen T et al (2001) S100A1: a regulator of myocardial contractility. Proc Natl Acad Sci U S A 98:13889–13894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Muller P, Coates PJ, Nenutil R, Trcka F, Hrstka R, Chovanec J, Brychtova V, Vojtesek B (2019) Tomm34 is commonly expressed in epithelial ovarian cancer and associates with tumour type and high FIGO stage. J Ovarian Res 12:30

    Article  PubMed  PubMed Central  Google Scholar 

  • Okada M, Hatakeyama T, Itoh H, Tokuta N, Tokumitsu H, Kobayashi R (2004) S100A1 is a novel molecular chaperone and a member of the Hsp70/Hsp90 multichaperone complex. J Biol Chem 279:4221–4233

    Article  CAS  PubMed  Google Scholar 

  • Ota A, Zhang J, Ping P, Han J, Wang Y (2010) Specific regulation of noncanonical p38alpha activation by Hsp90-Cdc37 chaperone complex in cardiomyocyte. Circ Res 106:1404–1412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paul A, Garcia YA, Zierer B, Patwardhan C, Gutierrez O, Hildenbrand Z, Harris DC, Balsiger HA, Sivils JC, Johnson JL, Buchner J, Chadli A, Cox MB (2014) The cochaperone SGTA (small glutamine-rich tetratricopeptide repeat-containing protein alpha) demonstrates regulatory specificity for the androgen, glucocorticoid, and progesterone receptors. J Biol Chem 289:15297–15308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pearl LH (2005) Hsp90 and Cdc37—a chaperone cancer conspiracy. Curr Opin Genet Dev 15:55–61

    Article  CAS  PubMed  Google Scholar 

  • Pei H, Li L, Fridley BL, Jenkins GD, Kalari KR, Lingle W, Petersen G, Lou Z, Wang L (2009) FKBP51 affects cancer cell response to chemotherapy by negatively regulating Akt. Cancer Cell 16:259–266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peng YJ, Huang JJ, Wu HH, Hsieh HY, Wu CY, Chen SC, Chen TY, Tang CY (2016) Regulation of CLC-1 chloride channel biosynthesis by FKBP8 and Hsp90beta. Sci Rep 6:32444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pratt WB, Toft DO (1997) Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr Rev 18:306–360

    CAS  PubMed  Google Scholar 

  • Prodromou C (2012) The 'active life' of Hsp90 complexes. Biochim Biophys Acta 1823:614–623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prodromou C, Siligardi G, O'Brien R, Woolfson DN, Regan L, Panaretou B, Ladbury JE, Piper PW, Pearl LH (1999) Regulation of Hsp90 ATPase activity by tetratricopeptide repeat (TPR)-domain co-chaperones. Embo J 18:754–762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reyes NL, Banks GB, Tsang M, Margineantu D, Gu H, Djukovic D, Chan J, Torres M, Liggitt HD, Hirenallur SD et al (2015) Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy. Proc Natl Acad Sci U S A 112:424–429

    Article  CAS  PubMed  Google Scholar 

  • Reynolds PD, Ruan Y, Smith DF, Scammell JG (1999) Glucocorticoid resistance in the squirrel monkey is associated with overexpression of the immunophilin FKBP51. J Clin Endocrinol Metab 84:663–669

    CAS  PubMed  Google Scholar 

  • Richter K, Muschler P, Hainzl O, Reinstein J, Buchner J (2003) 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Rivera-Calzada A, Pal M, Munoz-Hernandez H, Luque-Ortega JR, Gil-Carton D, Degliesposti G, Skehel JM, Prodromou C, Pearl LH, Llorca O (2017) The structure of the R2TP complex defines a platform for recruiting diverse client proteins to the HSP90 molecular chaperone system. Structure 25(1145-1152):e1144

    Google Scholar 

  • Ruiz-Estevez M, Staats J, Paatela E, Munson D, Katoku-Kikyo N, Yuan C, Asakura Y, Hostager R, Kobayashi H, Asakura A et al (2018) Promotion of myoblast differentiation by Fkbp5 via Cdk4 isomerization. Cell Rep 25(2537-2551):e2538

    Google Scholar 

  • Sager RA, Woodford MR, Mollapour M (2018) The mTOR independent function of Tsc1 and FNIPs. Trends Biochem Sci 43:935–937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sager RA, Woodford MR, Backe SJ, Makedon AM, Baker-Williams AJ, DiGregorio BT, Loiselle DR, Haystead TA, Zachara NE, Prodromou C et al (2019) Post-translational regulation of FNIP1 creates a rheostat for the molecular chaperone Hsp90. Cell Rep 26(1344-1356):e1345

    Google Scholar 

  • Sahasrabudhe P, Rohrberg J, Biebl MM, Rutz DA, Buchner J (2017) The plasticity of the Hsp90 co-chaperone system. Mol Cell 67(947-961):e945

    Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Scholz GM, Cartledge K, Hall NE (2001) Identification and characterization of Harc, a novel Hsp90-associating relative of Cdc37. J Biol Chem 276:30971–30979

    Article  CAS  PubMed  Google Scholar 

  • Schopf FH, Biebl MM, Buchner J (2017) The HSP90 chaperone machinery. Nature reviews Molecular cell biology 18:345–360

    Article  CAS  PubMed  Google Scholar 

  • Shelton LB, Koren J 3rd, Blair LJ (2017) Imbalances in the Hsp90 chaperone machinery: implications for tauopathies. Frontiers in Neuroscience 11:724

    Article  PubMed  PubMed Central  Google Scholar 

  • Shimoide T, Kawao N, Tamura Y, Morita H, Kaji H (2016) Novel roles of FKBP5 in muscle alteration induced by gravity change in mice. Biochem Biophys Res Commun 479:602–606

    Article  CAS  PubMed  Google Scholar 

  • Shirane M, Nakayama KI (2003) Inherent calcineurin inhibitor FKBP38 targets Bcl-2 to mitochondria and inhibits apoptosis. Nat Cell Biol 5:28–37

    Article  CAS  PubMed  Google Scholar 

  • Shirasu K (2009) The HSP90-SGT1 chaperone complex for NLR immune sensors. Annu Rev Plant Biol 60:139–164

    Article  CAS  PubMed  Google Scholar 

  • Smith JR, Clarke PA, de Billy E, Workman P (2009) Silencing the cochaperone CDC37 destabilizes kinase clients and sensitizes cancer cells to HSP90 inhibitors. Oncogene 28:157–169

    Article  CAS  PubMed  Google Scholar 

  • Srikakulam R, Liu L, Winkelmann DA (2008) Unc45b forms a cytosolic complex with Hsp90 and targets the unfolded myosin motor domain. PLoS ONE 3:e2137

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Srinivasan S, Meyer RD, Lugo R, Rahimi N (2013) Identification of PDCL3 as a novel chaperone protein involved in the generation of functional VEGF receptor 2. J Biol Chem 288:23171–23181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun L, Hartson SD, Matts RL (2015) Identification of proteins associated with Aha1 in HeLa cells by quantitative proteomics. Biochim Biophys Acta 1854:365–380

    Article  CAS  PubMed  Google Scholar 

  • Taguwa S, Okamoto T, Abe T, Mori Y, Suzuki T, Moriishi K, Matsuura Y (2008) Human butyrate-induced transcript 1 interacts with hepatitis C virus NS5A and regulates viral replication. J Virol 82:2631–2641

    Article  CAS  PubMed  Google Scholar 

  • Taipale M, Krykbaeva I, Koeva M, Kayatekin C, Westover KD, Karras GI, Lindquist S (2012) Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell 150:987–1001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taipale M, Tucker G, Peng J, Krykbaeva I, Lin ZY, Larsen B, Choi H, Berger B, Gingras AC, Lindquist S (2014) A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways. Cell 158:434–448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tanwar PS, Kaneko-Tarui T, Zhang L, Teixeira JM (2012) Altered LKB1/AMPK/TSC1/TSC2/mTOR signaling causes disruption of Sertoli cell polarity and spermatogenesis. Hum Mol Genet 21:4394–4405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tarone G, Brancaccio M (2015) The muscle-specific chaperone protein melusin is a potent cardioprotective agent. Basic Res Cardiol 110:10

    Article  PubMed  CAS  Google Scholar 

  • Topolska-Wos AM, Chazin WJ, Filipek A (2016) CacyBP/SIP—structure and variety of functions. Biochim Biophys Acta 1860:79–85

    Article  CAS  PubMed  Google Scholar 

  • Trcka F, Durech M, Man P, Hernychova L, Muller P, Vojtesek B (2014) The assembly and intermolecular properties of the Hsp70-Tomm34-Hsp90 molecular chaperone complex. J Biol Chem 289:9887–9901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Verba KA, Wang RY, Arakawa A, Liu Y, Shirouzu M, Yokoyama S, Agard DA (2016) Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase. Science 352:1542–1547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang X, Venable J, LaPointe P, Hutt DM, Koulov AV, Coppinger J, Gurkan C, Kellner W, Matteson J, Plutner H, Riordan JR, Kelly JW, Yates JR III, Balch WE (2006) Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell 127:803–815

    Article  CAS  PubMed  Google Scholar 

  • Wen Q, Tang EI, Lui WY, Lee WM, Wong CKC, Silvestrini B, Cheng CY (2018) Dynein 1 supports spermatid transport and spermiation during spermatogenesis in the rat testis. Am J Physiol Endocrinol Metab 315:E924–E948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woodford MR, Dunn DM, Blanden AR, Capriotti D, Loiselle D, Prodromou C, Panaretou B, Hughes PF, Smith A, Ackerman W, Haystead TA, Loh SN, Bourboulia D, Schmidt LS, Marston Linehan W, Bratslavsky G, Mollapour M (2016) The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding. Nat Commun 7:12037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woodford MR, Sager RA, Marris E, Dunn DM, Blanden AR, Murphy RL, Rensing N, Shapiro O, Panaretou B, Prodromou C, Loh SN, Gutmann DH, Bourboulia D, Bratslavsky G, Wong M, Mollapour M (2017) Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding of kinase and non-kinase clients. EMBO J 36:3650–3665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu Z, Moghaddas Gholami A, Kuster B (2012) Systematic identification of the HSP90 candidate regulated proteome. Mol Cell Proteomics 11(M111):016675

    PubMed  Google Scholar 

  • Yamamoto R, Hirono M, Kamiya R (2010) Discrete PIH proteins function in the cytoplasmic preassembly of different subsets of axonemal dyneins. J Cell Biol 190:65–71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang Y, Wang W, Li M, Gao Y, Zhang W, Huang Y, Zhuo W, Yan X, Liu W, Wang F, Chen D, Zhou T (2019) NudCL2 is an Hsp90 cochaperone to regulate sister chromatid cohesion by stabilizing cohesin subunits. Cell Mol Life Sci 76:381–395

    Article  CAS  PubMed  Google Scholar 

  • Young JC, Hoogenraad NJ, Hartl FU (2003) Molecular chaperones Hsp90 and Hsp70 deliver preproteins to the mitochondrial import receptor Tom70. Cell 112:41–50

    Article  CAS  PubMed  Google Scholar 

  • Zhang M, Windheim M, Roe SM, Peggie M, Cohen P, Prodromou C, Pearl LH (2005) Chaperoned ubiquitylation—crystal structures of the CHIP U box E3 ubiquitin ligase and a CHIP-Ubc13-Uev1a complex. Mol Cell 20:525–538

    Article  CAS  PubMed  Google Scholar 

  • Zhang W, Zhang S, Xiao C, Yang Y, Zhoucun A (2007) Mutation screening of the FKBP6 gene and its association study with spermatogenic impairment in idiopathic infertile men. Reproduction 133:511–516

    Article  CAS  PubMed  Google Scholar 

  • Zheng M, Cierpicki T, Burdette AJ, Utepbergenov D, Janczyk PL, Derewenda U, Stukenberg PT, Caldwell KA, Derewenda ZS (2011) Structural features and chaperone activity of the NudC protein family. J Mol Biol 409:722–741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu XJ, Liu X, Jin Q, Cai Y, Yang Y, Zhou T (2010) The L279P mutation of nuclear distribution gene C (NudC) influences its chaperone activity and lissencephaly protein 1 (LIS1) stability. J Biol Chem 285:29903–29910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 04/13/20. Additional information about proteins that interact with Hsp90 is available at http://www.picard.ch/downloads/Hsp90facts.pdf.

Funding

Research in the Johnson Lab is supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R01GM127675. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Biological Sciences, University of Idaho, Moscow, ID, 83844-3051, USA

    Marissa E. Dean & Jill L. Johnson

  2. Center for Reproductive Biology, University of Idaho, Moscow, ID, 83844-3051, USA

    Jill L. Johnson

Authors
  1. Marissa E. Dean
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jill L. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MED helped gather data and assisted with manuscript preparation. JLJ conceived the idea for the publication and wrote the manuscript.

Corresponding author

Correspondence to Jill L. Johnson.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Code availability

Not applicable.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(PDF 122 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dean, M.E., Johnson, J.L. Human Hsp90 cochaperones: perspectives on tissue-specific expression and identification of cochaperones with similar in vivo functions. Cell Stress and Chaperones 26, 3–13 (2021). https://doi.org/10.1007/s12192-020-01167-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12192-020-01167-0

Keywords

Search

Navigation