1932

Abstract

The Hsp40, Hsp70, and Hsp90 chaperone families are ancient, highly conserved, and critical to cellular protein homeostasis. Hsp40 chaperones can transfer their protein clients to Hsp70, and Hsp70 can transfer clients to Hsp90, but the functional benefits of these transfers are unclear. Recent structural and mechanistic work has opened up the possibility of uncovering how Hsp40, Hsp70, and Hsp90 work together as unified system. In this review, we compile mechanistic data on the ER J-domain protein 3 (ERdj3) (an Hsp40), BiP (an Hsp70), and Grp94 (an Hsp90) chaperones within the endoplasmic reticulum; what is known about how these chaperones work together; and gaps in this understanding. Using calculations, we examine how client transfer could impact the solubilization of aggregates, the folding of soluble proteins, and the triage decisions by which proteins are targeted for degradation. The proposed roles of client transfer among Hsp40-Hsp70-Hsp90 chaperones are new hypotheses, and we discuss potential experimental tests of these ideas.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-biophys-111622-091309
2023-05-09
2024-04-23
Loading full text...

Full text loading...

/deliver/fulltext/biophys/52/1/annurev-biophys-111622-091309.html?itemId=/content/journals/10.1146/annurev-biophys-111622-091309&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Amankwah YS, Collins P, Fleifil Y, Unruh E, Ruiz Márquez KJ et al. 2022. Grp94 works upstream of BiP in protein remodeling under heat stress. J. Mol. Biol. 434:19167762
    [Google Scholar]
  2. 2.
    Argon Y, Bresson SE, Marzec MT, Grimberg A. 2020. Glucose-regulated protein 94 (GRP94): a novel regulator of insulin-like growth factor production. Cells 9:81844
    [Google Scholar]
  3. 3.
    Behnke J, Mann MJ, Scruggs F-L, Feige MJ, Hendershot LM. 2016. Members of the Hsp70 family recognize distinct types of sequences to execute ER quality control. Mol. Cell. 63:5739–52
    [Google Scholar]
  4. 4.
    Biebl MM, Delhommel F, Faust O, Zak KM, Agam G et al. 2022. NudC guides client transfer between the Hsp40/70 and Hsp90 chaperone systems. Mol. Cell. 82:3555–69.e7
    [Google Scholar]
  5. 5.
    Cherepanova N, Shrimal S, Gilmore R. 2016. N-linked glycosylation and homeostasis of the endoplasmic reticulum. Curr. Opin. Cell Biol. 41:57–65
    [Google Scholar]
  6. 6.
    Deans EE, Kotler JLM, Wei W-S, Street TO. 2022. Electrostatics drive the molecular chaperone BiP to preferentially bind oligomerized states of a client protein. J. Mol. Biol. 434:167638
    [Google Scholar]
  7. 7.
    Eesmaa A, Yu L-Y, Göös H, Nõges K, Kovaleva V et al. 2021. The cytoprotective protein MANF promotes neuronal survival independently from its role as a GRP78 cofactor. J. Biol. Chem. 296:100295
    [Google Scholar]
  8. 8.
    Feige MJ, Groscurth S, Marcinowski M, Shimizu Y, Kessler H et al. 2009. An unfolded CH1 domain controls the assembly and secretion of IgG antibodies. Mol. Cell. 34:5569–79
    [Google Scholar]
  9. 9.
    Feige MJ, Hendershot LM, Buchner J. 2010. How antibodies fold. Trends Biochem. Sci. 35:4189–98
    [Google Scholar]
  10. 10.
    Genest O, Wickner S, Doyle SM. 2019. Hsp90 and Hsp70 chaperones: collaborators in protein remodeling. J. Biol. Chem. 294:62109–20
    [Google Scholar]
  11. 11.
    Georgiades P, Allan VJ, Wright GD, Woodman PG, Udommai P et al. 2017. The flexibility and dynamics of the tubules in the endoplasmic reticulum. Sci. Rep. 7:116474
    [Google Scholar]
  12. 12.
    Gidalevitz T, Biswas C, Ding H, Schneidman-Duhovny D, Wolfson HJ et al. 2004. Identification of the N-terminal peptide binding site of glucose-regulated protein 94. J. Biol. Chem. 279:1616543–52
    [Google Scholar]
  13. 13.
    Gidalevitz T, Stevens F, Argon Y. 2013. Orchestration of secretory protein folding by ER chaperones. Biochim. Biophys. Acta Mol. Cell Res. 1833:112410–24
    [Google Scholar]
  14. 14.
    Hendershot L, Bole D, Köhler G, Kearney JF. 1987. Assembly and secretion of heavy chains that do not associate posttranslationally with immunoglobulin heavy chain-binding protein. J. Cell Biol. 104:3761–67
    [Google Scholar]
  15. 15.
    Hennessy F, Nicoll WS, Zimmermann R, Cheetham ME, Blatch GL. 2005. Not all J domains are created equal: implications for the specificity of Hsp40-Hsp70 interactions. Protein Sci. 14:71697–709
    [Google Scholar]
  16. 16.
    Hosokawa N, Wada I, Nagasawa K, Moriyama T, Okawa K, Nagata K. 2008. Human XTP3-B forms an endoplasmic reticulum quality control scaffold with the HRD1-SEL1L ubiquitin ligase complex and BiP. J. Biol. Chem. 283:3020914–24
    [Google Scholar]
  17. 17.
    Huang B, Friedman LJ, Sun M, Gelles J, Street TO. 2019. Conformational cycling within the closed state of Grp94, an Hsp90-family chaperone. J. Mol. Biol. 431:173312–23
    [Google Scholar]
  18. 18.
    Huang B, Sun M, Hoxie R, Kotler JLM, Friedman LJ et al. 2022. The endoplasmic reticulum chaperone BiP is a closure-accelerating cochaperone of Grp94. PNAS 119:5e2118793119
    [Google Scholar]
  19. 19.
    Huck JD, Que NL, Hong F, Li Z, Gewirth DT. 2017. Structural and functional analysis of GRP94 in the closed state reveals an essential role for the pre-N domain and a potential client-binding site. Cell Rep. 20:122800–9
    [Google Scholar]
  20. 20.
    Jiang Y, Rossi P, Kalodimos CG. 2019. Structural basis for client recognition and activity of Hsp40 chaperones. Science 365:64591313–19
    [Google Scholar]
  21. 21.
    Jin Y, Kotler JLM, Wang S, Huang B, Halpin JC, Street TO. 2021. The ER chaperones BiP and Grp94 regulate the formation of insulin-like growth factor 2 (IGF2) oligomers. J. Mol. Biol. 433:166963
    [Google Scholar]
  22. 22.
    Karagöz GE, Rüdiger SGD. 2015. Hsp90 interaction with clients. Trends Biochem. Sci. 40:2117–25
    [Google Scholar]
  23. 23.
    Kityk R, Kopp J, Mayer MP. 2018. Molecular mechanism of J-domain-triggered ATP hydrolysis by Hsp70 chaperones. Mol. Cell. 69:2227–37.e4
    [Google Scholar]
  24. 24.
    Lai CW, Aronson DE, Snapp EL. 2010. BiP availability distinguishes states of homeostasis and stress in the endoplasmic reticulum of living cells. Mol. Biol. Cell. 21:121909–21
    [Google Scholar]
  25. 25.
    Liu B, Yang Y, Qiu Z, Staron M, Hong F et al. 2010. Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone. Nat. Commun. 1:79
    [Google Scholar]
  26. 26.
    Maji SK, Perrin MH, Sawaya MR, Jessberger S, Vadodaria K et al. 2009. Functional amyloids as natural storage of peptide hormones in pituitary secretory granules. Science 325:5938328–32
    [Google Scholar]
  27. 27.
    Marcinowski M, Höller M, Feige MJ, Baerend D, Lamb DC, Buchner J. 2011. Substrate discrimination of the chaperone BiP by autonomous and cochaperone-regulated conformational transitions. Nat. Struct. Mol. Biol. 18:2150–58
    [Google Scholar]
  28. 28.
    Matsuoka Y, Funahashi A, Ghosh S, Kitano H. 2014. Modeling and simulation using CellDesigner. Methods Mol. Biol. 1164:121–45
    [Google Scholar]
  29. 29.
    Mayer M, Reinstein J, Buchner J. 2003. Modulation of the ATPase cycle of BiP by peptides and proteins. J. Mol. Biol. 330:1137–44
    [Google Scholar]
  30. 30.
    Mayer MP, Gierasch LM. 2019. Recent advances in the structural and mechanistic aspects of Hsp70 molecular chaperones. J. Biol. Chem. 294:62085–97
    [Google Scholar]
  31. 31.
    Meunier L, Usherwood Y-K, Chung KT, Hendershot LM. 2002. A subset of chaperones and folding enzymes form multiprotein complexes in endoplasmic reticulum to bind nascent proteins. Mol. Biol. Cell. 13:124456–69
    [Google Scholar]
  32. 32.
    Morán Luengo T, Kityk R, Mayer MP, Rudiger SGD 2018. Hsp90 breaks the deadlock of the Hsp70 chaperone system. Mol. Cell. 70:3545–52.e9
    [Google Scholar]
  33. 33.
    Morán Luengo T, Mayer MP, Rüdiger SGD 2019. The Hsp70-Hsp90 chaperone cascade in protein folding. Trends Cell Biol. 29:2164–77
    [Google Scholar]
  34. 34.
    Noddings CM, Wang RY-R, Johnson JL, Agard DA 2022. Structure of Hsp90-p23-GR reveals the Hsp90 client-remodelling mechanism. Nature 601:7893465–69
    [Google Scholar]
  35. 35.
    Oikonomou C, Hendershot LM. 2020. Disposing of misfolded ER proteins: a troubled substrate's way out of the ER. Mol. Cell. Endocrinol. 500:110630
    [Google Scholar]
  36. 36.
    Packschies L, Theyssen H, Buchberger A, Bukau B, Goody RS, Reinstein J. 1997. GrpE accelerates nucleotide exchange of the molecular chaperone DnaK with an associative displacement mechanism. Biochemistry 36:3417–22
    [Google Scholar]
  37. 37.
    Parashar S, Chidambaram R, Chen S, Liem CR, Griffis E et al. 2021. Endoplasmic reticulum tubules limit the size of misfolded protein condensates. eLife 10:e71642
    [Google Scholar]
  38. 38.
    Perkins HT, Allan VJ, Waigh TA. 2021. Network organisation and the dynamics of tubules in the endoplasmic reticulum. Sci. Rep. 11:116230
    [Google Scholar]
  39. 39.
    Pobre KFR, Poet GJ, Hendershot LM. 2019. The endoplasmic reticulum (ER) chaperone BiP is a master regulator of ER functions: getting by with a little help from ERdj friends. J. Biol. Chem. 294:62098–108
    [Google Scholar]
  40. 40.
    Powers ET, Powers DL, Gierasch LM. 2012. FoldEco: a model for proteostasis in E. coli. Cell Rep. 1:3265–76
    [Google Scholar]
  41. 41.
    Pratt WB, Galigniana MD, Morishima Y, Murphy PJM. 2004. Role of molecular chaperones in steroid receptor action. Essays Biochem. 40:41–58
    [Google Scholar]
  42. 42.
    Preissler S, Rato C, Chen R, Antrobus R, Ding S et al. 2015. AMPylation matches BiP activity to client protein load in the endoplasmic reticulum. eLife 4:e12621
    [Google Scholar]
  43. 43.
    Preissler S, Rato C, Yan Y, Perera LA, Czako A, Ron D. 2020. Calcium depletion challenges endoplasmic reticulum proteostasis by destabilising BiP-substrate complexes. eLife 9:e62601
    [Google Scholar]
  44. 44.
    Rodina A, Wang T, Yan P, Gomes E, Dunphy MP et al. 2016. The epichaperome is an integrated chaperome network that facilitates tumour survival. Nature 538:397–401
    [Google Scholar]
  45. 45.
    Rodriguez F, Arsène-Ploetze F, Rist W, Rüdiger S, Schneider-Mergener J et al. 2008. Molecular basis for regulation of the heat shock transcription factor sigma32 by the DnaK and DnaJ chaperones. Mol. Cell. 32:3347–58
    [Google Scholar]
  46. 46.
    Santra M, Farrell DW, Dill KA. 2017. Bacterial proteostasis balances energy and chaperone utilization efficiently. PNAS 114:13E2654–61
    [Google Scholar]
  47. 47.
    Shen Y, Hendershot LM. 2005. ERdj3, a stress-inducible endoplasmic reticulum DnaJ homologue, serves as a cofactor for BiP's interactions with unfolded substrates. Mol. Biol. Cell. 16:140–50
    [Google Scholar]
  48. 48.
    Shim SM, Choi HR, Sung KW, Lee YJ, Kim ST et al. 2018. The endoplasmic reticulum-residing chaperone BiP is short-lived and metabolized through N-terminal arginylation. Sci. Signal. 11:511eaan0630
    [Google Scholar]
  49. 49.
    Siegenthaler KD, Pareja KA, Wang J, Sevier CS. 2017. An unexpected role for the yeast nucleotide exchange factor Sil1 as a reductant acting on the molecular chaperone BiP. eLife 6:e24141
    [Google Scholar]
  50. 50.
    Stankiewicz M, Nikolay R, Rybin V, Mayer MP. 2010. CHIP participates in protein triage decisions by preferentially ubiquitinating Hsp70-bound substrates. FEBS J. 277:163353–67
    [Google Scholar]
  51. 51.
    Summers DW, Douglas PM, Ramos CHI, Cyr DM. 2009. Polypeptide transfer from Hsp40 to Hsp70 molecular chaperones. Trends Biochem. Sci. 34:5230–33
    [Google Scholar]
  52. 52.
    Sun M, Kotler JLM, Liu S, Street TO. 2019. The endoplasmic reticulum (ER) chaperones BiP and Grp94 selectively associate when BiP is in the ADP conformation. J. Biol. Chem. 294:166387–96
    [Google Scholar]
  53. 53.
    Suntharalingam A, Abisambra JF, O'Leary JC, Koren J, Zhang B et al. 2012. Glucose-regulated protein 94 triage of mutant myocilin through endoplasmic reticulum-associated degradation subverts a more efficient autophagic clearance mechanism. J. Biol. Chem. 287:4840661–69
    [Google Scholar]
  54. 54.
    Vanhove M, Usherwood Y-K, Hendershot LM. 2001. Unassembled Ig heavy chains do not cycle from BiP in vivo but require light chains to trigger their release. Immunity 15:1105–14
    [Google Scholar]
  55. 55.
    Verba KA, Wang RY-R, Arakawa A, Liu Y, Shirouzu M et al. 2016. Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase. Science 352:62931542–47
    [Google Scholar]
  56. 56.
    Wang J, Sevier CS. 2016. Formation and reversibility of BiP protein cysteine oxidation facilitate cell survival during and post oxidative stress. J. Biol. Chem. 291:147541–57
    [Google Scholar]
  57. 57.
    Wang RY-R, Noddings CM, Kirschke E, Myasnikov AG, Johnson JL, Agard DA. 2022. Structure of Hsp90-Hsp70-Hop-GR reveals the Hsp90 client-loading mechanism. Nature 601:7893460–64
    [Google Scholar]
  58. 58.
    West M, Zurek N, Hoenger A, Voeltz GK. 2011. A 3D analysis of yeast ER structure reveals how ER domains are organized by membrane curvature. J. Cell Biol. 193:2333–46
    [Google Scholar]
  59. 59.
    Wieteska L, Shahidi S, Zhuravleva A. 2017. Allosteric fine-tuning of the conformational equilibrium poises the chaperone BiP for post-translational regulation. eLife 6:e29430
    [Google Scholar]
  60. 60.
    Wilkins S, Choglay AA, Chapple JP, van der Spuy J, Rhie A et al. 2010. The binding of the molecular chaperone Hsc70 to the prion protein PrP is modulated by pH and copper. Int. J. Biochem. Cell Biol. 42:71226–32
    [Google Scholar]
  61. 61.
    Winkler J, Tyedmers J, Bukau B, Mogk A. 2012. Hsp70 targets Hsp100 chaperones to substrates for protein disaggregation and prion fragmentation. J. Cell Biol. 198:3387–404
    [Google Scholar]
  62. 62.
    Wu X, Rapoport TA. 2018. Mechanistic insights into ER-associated protein degradation. Curr. Opin. Cell Biol. 53:22–28
    [Google Scholar]
  63. 63.
    Wu X, Siggel M, Ovchinnikov S, Mi W, Svetlov V et al. 2020. Structural basis of ER-associated protein degradation mediated by the Hrd1 ubiquitin ligase complex. Science 368:6489eaaz2449
    [Google Scholar]
  64. 64.
    Yamamoto K, Sato T, Matsui T, Sato M, Okada T et al. 2007. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6α and XBP1. Dev. Cell. 13:3365–76
    [Google Scholar]
  65. 65.
    Yan M, Li J, Sha B 2011. Structural analysis of the Sil1-Bip complex reveals the mechanism for Sil1 to function as a nucleotide-exchange factor. Biochem. J. 438:3447–55
    [Google Scholar]
  66. 66.
    Yan Y, Rato C, Rohland L, Preissler S, Ron D 2019. MANF antagonizes nucleotide exchange by the endoplasmic reticulum chaperone BiP. Nat. Commun. 10:541
    [Google Scholar]
  67. 67.
    Yang J, Nune M, Zong Y, Zhou L, Liu Q. 2015. Close and allosteric opening of the polypeptide-binding site in a human Hsp70 chaperone BiP. Structure 23:122191–203
    [Google Scholar]
  68. 68.
    Yang J, Zong Y, Su J, Li H, Zhu H et al. 2017. Conformation transitions of the polypeptide-binding pocket support an active substrate release from Hsp70s. Nat. Commun. 8:1201
    [Google Scholar]
/content/journals/10.1146/annurev-biophys-111622-091309
Loading
/content/journals/10.1146/annurev-biophys-111622-091309
Loading

Data & Media loading...

Supplemental Material

Supplementary Data

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error