Function, evolution, and structure of J-domain proteins

Abstract

Hsp70 chaperone systems are very versatile machines present in nearly all living organisms and in nearly all intracellular compartments. They function in many fundamental processes through their facilitation of protein (re)folding, trafficking, remodeling, disaggregation, and degradation. Hsp70 machines are regulated by co-chaperones. J-domain containing proteins (JDPs) are the largest family of Hsp70 co-chaperones and play a determining role functionally specifying and directing Hsp70 functions. Many features of JDPs are not understood; however, a number of JDP experts gathered at a recent CSSI-sponsored workshop in Gdansk (Poland) to discuss various aspects of J-domain protein function, evolution, and structure. In this report, we present the main findings and the consensus reached to help direct future developments in the field of Hsp70 research.

This is a preview of subscription content, access via your institution.

References

  1. Baaklini I, Wong MJ, Hantouche C, Patel Y, Shrier A, Young JC (2012) The DNAJA2 substrate release mechanism is essential for chaperone-mediated folding. J Biol Chem 287(50):41939–41954

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Behnke J, Mann MJ, Scruggs FL, Feige MJ, Hendershot LM (2016) Members of the Hsp70 family recognize distinct types of sequences to execute ER quality control. Mol Cell 63(5):739–752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bracher A, Verghese J (2015) The nucleotide exchange factors of Hsp70 molecular chaperones. Front Mol Biosci 2:10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Cheetham ME, Caplan AJ (1998) Structure, function and evolution of DnaJ: conservation and adaptation of chaperone function. Cell Stress Chaperones 3(1):28–36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chen KC, Qu S, Chowdhury S, Noxon IC, Schonhoft JD, Plate L, Powers ET, Kelly JW, Lander GC, Wiseman RL (2017) The endoplasmic reticulum HSP40 co-chaperone ERdj3/DNAJB11 assembles and functions as a tetramer. EMBO J 36(15):2296–2309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Craig EA, Marszalek J (2017) How do J-proteins get Hsp70 to do so many different things? Trends Biochem Sci 42(5):355–368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Craig EA (2018) Hsp70 at the membrane: driving protein translocation. BMC Biol 16(1):11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cyr DM, Langer T, Douglas MG (1994) DnaJ-like proteins: molecular chaperones and specific regulators of Hsp70. Trends Biochem Sci 19(4):176–181

    Article  CAS  PubMed  Google Scholar 

  9. Delewski W, Paterkiewicz B, Manicki M, Schilke B, Tomiczek B, Ciesielski SJ, Nierzwicki L, Czub J, Dutkiewicz R, Craig EA, Marszalek J (2016) Iron–sulfur cluster biogenesis chaperones: evidence for emergence of mutational robustness of a highly specific protein–protein interaction. Mol Biol Evol 33(3):643–656

    Article  CAS  PubMed  Google Scholar 

  10. Finka A, Mattoo RU, Goloubinoff P (2011) Meta-analysis of heat- and chemically upregulated chaperone genes in plant and human cells. Cell Stress Chaperones 16(1):15–31

    Article  CAS  PubMed  Google Scholar 

  11. Gowda NKC, Kaimal JM, Kityk R, Daniel C, Liebau J, Öhman M, Mayer MP, Andréasson C (2018) Nucleotide exchange factors Fes1 and HspBP1 mimic substrate to release misfolded proteins from Hsp70. Nat Struct Mol Biol 25(1):83–89

    Article  CAS  PubMed  Google Scholar 

  12. Grove DE, Fan CY, Ren HY, Cyr DM (2011) The endoplasmic reticulum-associated Hsp40 DNAJB12 and Hsc70 cooperate to facilitate RMA1 E3-dependent degradation of nascent CFTRDeltaF508. Mol Biol Cell 22(3):301–314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hageman J, Kampinga HH (2009) Computational analysis of the human HSPH/HSPA/DNAJ family and cloning of a human HSPH/HSPA/DNAJ expression library. Cell Stress Chaperones 14(1):1–21

    Article  CAS  PubMed  Google Scholar 

  14. Hageman J, Rujano MA, van Waarde MA, Kakkar V, Dirks RP, Govorukhina N, Oosterveld-Hut HM, Lubsen NH, Kampinga HH (2010) A DNAJB chaperone subfamily with HDAC-dependent activities suppresses toxic protein aggregation. Mol Cell 37(3):355–369

    Article  CAS  PubMed  Google Scholar 

  15. Hassdenteufel S, Johnson N, Paton AW, Paton JC, High S, Zimmermann R (2018) Chaperone-mediated Sec61 channel gating during ER import of small precursor proteins overcomes Sec61 inhibitor-reinforced energy barrier. Cell Rep 23(5):1373–1386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kampinga HH, Craig EA (2010) The HSP70 chaperone machinery: J proteins as drivers of functional specificity. Nat Rev Mol Cell Biol 11(8):579–592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kakkar V, Meister-Broekema M, Minoia M, Carra S, Kampinga HH (2014) Barcoding heat shock proteins to human diseases: looking beyond the heat shock response. Dis Model Mech 7(4):421–434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kakkar V, Mansson C, de Mattos EP, Bergink S, van der Zwaag M, van Waarde MAWH, Kloosterhuis NJ, Melki R, van Cruchten RTP, Al-Karadaghi S, Arosio P, Dobson CM, Knowles TPJ, Bates GP, van Deursen JM, Linse S, van de Sluis B, Emanuelsson C, Kampinga HH (2016) The S/T-rich motif in the DNAJB6 chaperone delays polyglutamine aggregation and the onset of disease in a mouse model. Mol Cell 62(2):272–283

    Article  CAS  PubMed  Google Scholar 

  19. Kirstein J, Arnsburg K, Scior A, Szlachcic A, Guilbride DL, Morimoto RI, Bukau B, Nillegoda NB (2017) In vivo properties of the disaggregase function of J-proteins and Hsc70 in Caenorhabditis elegans stress and aging. Aging Cell 16:1414–1424

  20. Kityk R, Kopp J, Mayer MP (2018) Molecular mechanism of J-domain-triggered ATP hydrolysis by Hsp70 chaperones. Mol Cell 69(2):227–237

    Article  CAS  PubMed  Google Scholar 

  21. Labbadia J, Novoselov SS, Bett JS, Weiss A, Paganetti P, Bates GP, Cheetham ME (2012) Suppression of protein aggregation by chaperone modification of high molecular weight complexes. Brain 135(Pt 4):1180–1196

    Article  PubMed  PubMed Central  Google Scholar 

  22. Li K, Jiang Q, Bai X, Yang YF, Ruan MY, Cai SQ (2017) Tetrameric assembly of K(+) channels requires ER-located chaperone proteins. Mol Cell 65(1):52–65

    Article  CAS  PubMed  Google Scholar 

  23. Liberek K, Marszalek J, Ang D, Georgopoulos C, Zylicz M (1991) Escherichia coli DnaJ and GrpE heat shock proteins jointly stimulate ATPase activity of DnaK. Proc Natl Acad Sci U S A 88:2874–2878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Linxweiler M, Schick B, Zimmermann R (2017) Let’s talk about Secs: Sec61, Sec62 and Sec63 in signal transduction, oncology and personalized medicine. Signal Transduct Target Ther 2:17002

    Article  PubMed  PubMed Central  Google Scholar 

  25. Månsson C, van Cruchten RTP, Weininger U, Yang X, Cukalevski R, Arosio P, Dobson CM, Knowles T, Akke M, Linse S, Emanuelsson C, Conserved S (2018) T residues of the human chaperone DNAJB6 are required for effective inhibition of Aβ42 amyloid fibril formation. Biochemistry 57(32):4891–4902

    Article  CAS  PubMed  Google Scholar 

  26. Malinverni D, Jost Lopez A, De Los Rios P, Hummer G, Barducci A (2017) Modeling Hsp70/Hsp40 interaction by multi-scale molecular simulations and coevolutionary sequence analysis. Elife:6

  27. Mayer MP (2018) Intra-molecular pathways of allosteric control in Hsp70s. Philos Trans R Soc Lond Ser B Biol Sci 373(1749):20170183

    Article  CAS  Google Scholar 

  28. Melnyk A, Rieger H, Zimmermann R (2015) Co-chaperones of the mammalian endoplasmic reticulum. Subcell Biochem 78:179–200

    Article  CAS  PubMed  Google Scholar 

  29. Mok SA, Condello C, Freilich R, Gillies A, Arhar T, Oroz J, Kadavath H, Julien O, Assimon VA, Rauch JN, Dunyak BM, Lee J, Tsai FTF, Wilson MR, Zweckstetter M, Dickey CA, Gestwicki JE (2018) Mapping interactions with the chaperone network reveals factors that protect against tau aggregation. Nat Struct Mol Biol 25(5):384–393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Nillegoda NB, Kirstein J, Szlachcic A, Berynskyy M, Stank A, Stengel F, Arnsburg K, Gao X, Scior A, Aebersold R, Guilbride DL, Wade RC, Morimoto RI, Mayer MP, Bukau B (2015) Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation. Nature 524(7564):247–251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nillegoda NB, Stank A, Malinverni D, Alberts N, Szlachcic A, Barducci A, De Los Rios P, Wade RC, Bukau B. Evolution of an intricate J-protein network driving protein disaggregation in eukaryotes. elife 2017;6. pii: e24560. https://doi.org/10.7554/eLife.24560

  32. Nillegoda NB, Wentink AS, Bukau B (2018) Protein disaggregation in multicellular organisms. Trends Biochem Sci 43(4):285–300

    Article  CAS  PubMed  Google Scholar 

  33. Perales-Calvo J, Muga A, Moro F (2010) Role of DnaJ G/F-rich domain in conformational recognition and binding of protein substrates. J Biol Chem 285(44):34231–34239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Perrody E, Cirinesi AM, Desplats C, Keppel F, Schwager F, Tranier S, Georgopoulos C, Genevaux P (2012) A bacteriophage-encoded J-domain protein interacts with the DnaK/Hsp70 chaperone and stabilizes the heat-shock factor σ32 of Escherichia coli. PLoS Genet 8(11):e1003037. https://doi.org/10.1371/journal.pgen.1003037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pulido P, Leister D (2018) Novel DNAJ-related proteins in Arabidopsis thaliana. New Phytol 217(2):480–490

    Article  CAS  PubMed  Google Scholar 

  36. Rauch JN, Zuiderweg ER, Gestwicki JE (2016) Non-canonical interactions between heat shock cognate protein 70 (Hsc70) and Bcl2-associated Anthanogene (BAG) co-chaperones are important for client release. J Biol Chem 291(38):19848–19857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rosam M, Krader D, Nickels C, Hochmair J, Back KC, Agam G, Barth A, Zeymer C, Hendrix J, Schneider M, Antes I, Reinstein J, Lamb DC, Buchner J (2018) Bap (Sil1) regulates the molecular chaperone BiP by coupling release of nucleotide and substrate. Nat Struct Mol Biol 25(1):90–100

    Article  CAS  PubMed  Google Scholar 

  38. Rosenzweig R, Sekhar A, Nagesh J, Kay LE. Promiscuous binding by Hsp70 results in conformational heterogeneity and fuzzy chaperone-substrate ensembles. elife 2017;6. pii: e28030. https://doi.org/10.7554/eLife.28030

  39. Ruggieri A, Saredi S, Zanotti S, Pasanisi MB, Maggi L, M1 M (2016) DNAJB6 myopathies: focused review on an emerging and expanding group of myopathies. Front Mol Biosci 3(63) eCollection 2016

  40. Sahi C, Kominek J, Ziegelhoffer T, Yu HY, Baranowski M, Marszalek J, Craig EA (2013) Sequential duplications of an ancient member of the DnaJ-family expanded the functional chaperone network in the eukaryotic cytosol. Mol Biol Evol 30(5):985–998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Scior A, Buntru A, Arnsburg K, Ast A, Iburg M, Juenemann K, Pigazzini ML, Mlody B, Puchkov D, Priller J, Wanker EE, Prigione A, Kirstein J (2018) Complete suppression of Htt fibrilization and disaggregation of Htt fibrils by a trimeric chaperone complex. EMBO J 37(2):282–299

    Article  CAS  PubMed  Google Scholar 

  42. Sharma SK, De los Rios P, Christen P, Lustig A, Goloubinoff P (2010) The kinetic parameters and energy cost of the Hsp70 chaperone as a polypeptide unfoldase. Nat Chem Biol 6(12):914–920

    Article  CAS  PubMed  Google Scholar 

  43. Soderberg CAG, Mannsson C, Bernfur K, Rutsdottir G, Harmark J, Rajan S, Al-Karadaghi S, Rasmussen M, Hajrup P, Hebert H, Emanuelsson C (2018) Structural modelling of the DNAJB6 oligomeric chaperone shows a peptide-binding cleft lined with conserved S/T-residues at the dimer interface. Sci Rep 8(1):5199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Swain JF, Gierasch LM (2006) The changing landscape of protein allostery. Curr Opin Struct Biol 16(1):102–108

    Article  CAS  PubMed  Google Scholar 

  45. Taylor IR, Dunyak BM, Komiyama T, Shao H, Ran X, Assimon VA, Kalyanaraman C, Rauch JN, Jacobson MP, Zuiderweg ERP, Gestwicki JE (2018) High-throughput screen for inhibitors of protein-protein interactions in a reconstituted heat shock protein 70 (Hsp70) complex. J Biol Chem 293(11):4014–4025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ushioda R, Miyamoto A, Inoue M, Watanabe S, Okumura M, Maegawa KI, Uegaki K, Fujii S, Fukuda Y, Umitsu M, Takagi J, Inaba K, Mikoshiba K, Nagata K (2016) Redox-assisted regulation of Ca2+ homeostasis in the endoplasmic reticulum by disulfide reductase ERdj5. Proc Natl Acad Sci U S A 113(41):E6055–E6063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wall D, Zylicz M, Georgopoulos C (1995) The conserved G/F motif of the DnaJ chaperone is necessary for the activation of the substrate binding properties of the DnaK chaperone. J Biol Chem 270(5):2139–2144

    Article  CAS  PubMed  Google Scholar 

  48. Wawrzynow B, Zylicz A, Zylicz M (2018) Chaperoning the guardian of the genome. The two-faced role of molecular chaperones in p53 tumor suppressor action. Biochim Biophys Acta Rev Cancer 1869(2):161–174

    Article  CAS  PubMed  Google Scholar 

  49. Yan W, Craig EA (1999) The glycine-phenylalanine-rich region determines the specificity of the yeast Hsp40 Sis1. Mol Cell Biol 19(11):7751–7758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zarouchlioti C, Parfitt DA, Li W, Gittings LM, Cheetham ME (2018) DNAJ proteins in neurodegeneration: essential and protective factors. Philos Trans R Soc Lond Ser B Biol Sci 373(1738):20160534

    Article  CAS  Google Scholar 

  51. Zhang Y, Sinning I, Rospert S (2017) Two chaperones locked in an embrace: structure and function of the ribosome-associated complex RAC. Nat Struct Mol Biol 24(8):611–619

    Article  CAS  PubMed  Google Scholar 

  52. Zuiderweg ER, Bertelsen EB, Rousaki A, Mayer MP, Gestwicki JE, Ahmad A (2013) Allostery in the Hsp70 chaperone proteins. Top Curr Chem 328:99–153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

The organizers would like to thank the Cell Stress Society International (CSSI) for their financial support of the workshop. We also thank the Rector of the University of Gdansk, the Dean of the Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, and The University Medical Center Groningen for financial support. During organization of this workshop JM was supported by Polish National Science Center Grant DEC-2012/06/A/NZ1/00002.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Harm H. Kampinga.

Electronic supplementary material

ESM 1

(PDF 1089 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kampinga, H.H., Andreasson, C., Barducci, A. et al. Function, evolution, and structure of J-domain proteins. Cell Stress and Chaperones 24, 7–15 (2019). https://doi.org/10.1007/s12192-018-0948-4

Download citation

Keywords

  • Heat shock protein 70 (Hsp70)
  • J-domain proteins (JDPs)
  • 8-stranded β-sandwich domain (SBDβ)