Biophysical Reviews

, Volume 10, Issue 2, pp 339–345 | Cite as

Prefoldin, a jellyfish-like molecular chaperone: functional cooperation with a group II chaperonin and beyond

  • Muhamad Sahlan
  • Tamotsu Zako
  • Masafumi Yohda


Prefoldin is a hexameric molecular chaperone found in the cytosol of archaea and eukaryotes. Its hexameric complex is built from two related classes of subunits and has the appearance of a jellyfish: its body consists of a double beta-barrel assembly with six long tentacle-like coiled coils protruding from it. Using the tentacles, prefoldin captures an unfolded protein substrate and transfers it to a group II chaperonin. The prefoldin-group II chaperonin system is thought to be important for the folding of newly synthesized proteins and for their maintenance, or proteostasis, in the cytosol. Based on structural information of archaeal prefoldins, the mechanisms of substrate recognition and prefoldin-chaperonin cooperation have been investigated. In contrast, the role and mechanism of eukaryotic PFDs remain unknown. Recent studies have shown that prefoldin plays an important role in proteostasis and is involved in various diseases. In this paper, we review a series of studies on the molecular mechanisms of archaeal prefoldins and introduce recent findings about eukaryotic prefoldin.


Molecular chaperone Prefoldin Chaperonin 



This work partly supported by grants-in-aids for scientific research (JP16H04572, JP16H00753 and JP15J08261) from the Ministry of Education, Science, Sports, and Culture of Japan and the World Class Professor Program (No. 168.A10/D2/KP/2017) from Ministry of Research, Technology and Higher Education of the Republic of Indonesia.

Compliance with ethical standards

Conflict of interest

Muhamad Sahlan declares that he has no conflict of interest. Tamotsu Zako declares that he has no conflict of interest. Masafumi Yohda declares that he has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. Abe A et al (2013) Prefoldin plays a role as a clearance factor in preventing proteasome inhibitor-induced protein aggregation. J Biol Chem 288:27764–27776. CrossRefPubMedPubMedCentralGoogle Scholar
  2. Aikawa Y, Kida H, Nishitani Y, Miki K (2015) Expression, purification, crystallization and X-ray diffraction studies of the molecular chaperone prefoldin from Homo sapiens. Acta Crystallogr F Struct Biol Commun 71:1189–1193. CrossRefPubMedPubMedCentralGoogle Scholar
  3. Danno A et al (2008) Expression profiles and physiological roles of two types of prefoldins from the hyperthermophilic archaeon Thermococcus kodakaraensis. J Mol Biol 382:298–311. CrossRefPubMedGoogle Scholar
  4. Ditzel L, Lowe J, Stock D, Stetter KO, Huber H, Huber R, Steinbacher S (1998) Crystal structure of the thermosome, the archaeal chaperonin and homolog of CCT. Cell 93:125–138CrossRefPubMedGoogle Scholar
  5. Fujiwara S, Aki R, Yoshida M, Higashibata H, Imanaka T, Fukuda W (2008) Expression profiles and physiological roles of two types of molecular chaperonins from the hyperthermophilic archaeon Thermococcus kodakarensis. Appl Environ Microbiol 74:7306–7312. CrossRefPubMedPubMedCentralGoogle Scholar
  6. Geissler S, Siegers K, Schiebel E (1998) A novel protein complex promoting formation of functional alpha- and gamma-tubulin. EMBO J 17:952–966. CrossRefPubMedPubMedCentralGoogle Scholar
  7. Gu J et al (2015) URI expression in cervical cancer cells is associated with higher invasion capacity and resistance to cisplatin. Am J Cancer Res 5:1353–1367PubMedPubMedCentralGoogle Scholar
  8. Gutsche I, Essen LO, Baumeister W (1999) Group II chaperonins: new TRiC(k)s and turns of a protein folding machine. J Mol Biol 293:295–312. CrossRefPubMedGoogle Scholar
  9. Hansen WJ, Cowan NJ, Welch WJ (1999) Prefoldin-nascent chain complexes in the folding of cytoskeletal proteins. J Cell Biol 145:265–277CrossRefPubMedPubMedCentralGoogle Scholar
  10. Hartl FU, Hayer-Hartl M (2002) Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295:1852–1858. CrossRefPubMedGoogle Scholar
  11. Horwich AL, Fenton WA, Chapman E, Farr GW (2007) Two families of chaperonin: physiology and mechanism. Annu Rev Cell Dev Biol 23:115–145. CrossRefPubMedGoogle Scholar
  12. Hu X et al (2016) URI promotes gastric cancer cell motility, survival, and resistance to adriamycin in vitro. Am J Cancer Res 6:1420–1430PubMedPubMedCentralGoogle Scholar
  13. Iizuka R, So S, Inobe T, Yoshida T, Zako T, Kuwajima K, Yohda M (2004) Role of the helical protrusion in the conformational change and molecular chaperone activity of the archaeal group II chaperonin. J Biol Chem 279:18834–18839. CrossRefPubMedGoogle Scholar
  14. Iizuka R et al (2008) Functional characterization of recombinant prefoldin complexes from a hyperthermophilic archaeon, Thermococcus sp. strain KS-1. J Mol Biol 377:972–983. CrossRefPubMedGoogle Scholar
  15. Kurimoto E et al (2007) Dynamics of group II chaperonin and prefoldin probed by (13)C NMR spectroscopy. Proteins 70:1257–1263CrossRefGoogle Scholar
  16. Leroux MR et al (1999) MtGimC, a novel archaeal chaperone related to the eukaryotic chaperonin cofactor GimC/prefoldin. EMBO J 18:6730–6743. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Lipinski KA, Britschgi C, Schrader K, Christinat Y, Frischknecht L, Krek W (2016) Colorectal cancer cells display chaperone dependency for the unconventional prefoldin URI1. Oncotarget 7:29635–29647. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Lopez V et al (2013) Identification of prefoldin amplification (1q23.3-q24.1) in bladder cancer using comparative genomic hybridization (CGH) arrays of urinary DNA. J Transl Med 11:182. CrossRefPubMedPubMedCentralGoogle Scholar
  19. Lundin VF, Stirling PC, Gomez-Reino J, Mwenifumbo JC, Obst JM, Valpuesta JM, Leroux MR (2004) Molecular clamp mechanism of substrate binding by hydrophobic coiled-coil residues of the archaeal chaperone prefoldin. Proc Natl Acad Sci U S A 101:4367–4372. CrossRefPubMedPubMedCentralGoogle Scholar
  20. Martin-Benito J et al (2002) Structure of eukaryotic prefoldin and of its complexes with unfolded actin and the cytosolic chaperonin CCT. EMBO J 21:6377–6386CrossRefPubMedPubMedCentralGoogle Scholar
  21. Martin-Benito J et al (2007) Divergent substrate-binding mechanisms reveal an evolutionary specialization of eukaryotic prefoldin compared to its archaeal counterpart. Structure 15:101–110. CrossRefPubMedGoogle Scholar
  22. Meyer AS, Gillespie JR, Walther D, Millet IS, Doniach S, Frydman J (2003) Closing the folding chamber of the eukaryotic chaperonin requires the transition state of ATP hydrolysis. Cell 113:369–381CrossRefPubMedGoogle Scholar
  23. Miyoshi N et al (2010) Abnormal expression of PFDN4 in colorectal cancer: a novel marker for prognosis. Ann Surg Oncol 17:3030–3036. CrossRefPubMedGoogle Scholar
  24. Ohtaki A et al (2008) Structure and molecular dynamics simulation of archaeal prefoldin: the molecular mechanism for binding and recognition of nonnative substrate proteins. J Mol Biol 376:1130–1141. CrossRefPubMedGoogle Scholar
  25. Okochi M, Yoshida T, Maruyama T, Kawarabayasi Y, Kikuchi H, Yohda M (2002) Pyrococcus prefoldin stabilizes protein-folding intermediates and transfers them to chaperonins for correct folding. Biochem Biophys Res Commun 291:769–774CrossRefPubMedGoogle Scholar
  26. Okochi M et al (2004) Kinetics and binding sites for interaction of the prefoldin with a group II chaperonin: contiguous non-native substrate and chaperonin binding sites in the archaeal prefoldin. J Biol Chem 279:31788–31795. CrossRefPubMedGoogle Scholar
  27. Sahlan M et al (2010) Thermodynamic characterization of the interaction between prefoldin and group II chaperonin. J Mol Biol 399:628–636. CrossRefPubMedGoogle Scholar
  28. Shomura Y, Yoshida T, Iizuka R, Maruyama T, Yohda M, Miki K (2004) Crystal structures of the group II chaperonin from Thermococcus strain KS-1: steric hindrance by the substituted amino acid, and inter-subunit rearrangement between two crystal forms. J Mol Biol 335:1265–1278CrossRefPubMedGoogle Scholar
  29. Siegert R, Leroux MR, Scheufler C, Hartl FU, Moarefi I (2000) Structure of the molecular chaperone prefoldin: unique interaction of multiple coiled coil tentacles with unfolded proteins. Cell 103:621–632CrossRefPubMedGoogle Scholar
  30. Simons CT, Staes A, Rommelaere H, Ampe C, Lewis SA, Cowan NJ (2004) Selective contribution of eukaryotic prefoldin subunits to actin and tubulin binding. J Biol Chem 279:4196–4203. CrossRefPubMedGoogle Scholar
  31. Sorgjerd KM et al (2013) Human prefoldin inhibits amyloid-beta (Abeta) fibrillation and contributes to formation of nontoxic Abeta aggregates. Biochemistry 52:3532–3542. CrossRefPubMedGoogle Scholar
  32. Tashiro E et al (2013) Prefoldin protects neuronal cells from polyglutamine toxicity by preventing aggregation formation. J Biol Chem 288:19958–19972. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Vainberg IE, Lewis SA, Rommelaere H, Ampe C, Vandekerckhove J, Klein HL, Cowan NJ (1998) Prefoldin, a chaperone that delivers unfolded proteins to cytosolic chaperonin. Cell 93:863–873CrossRefPubMedGoogle Scholar
  34. Wang P et al (2015) PFDN1, an indicator for colorectal cancer prognosis, enhances tumor cell proliferation and motility through cytoskeletal reorganization. Med Oncol 32:264. CrossRefPubMedGoogle Scholar
  35. Wang D et al (2017) Prefoldin 1 promotes EMT and lung cancer progression by suppressing cyclin a expression. Oncogene 36:885–898. CrossRefPubMedGoogle Scholar
  36. Whitehead TA, Boonyaratanakornkit BB, Hollrigl V, Clark DS (2007) A filamentous molecular chaperone of the prefoldin family from the deep-sea hyperthermophile Methanocaldococcus jannaschii. Protein Sci 16:626–634. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Whitehead TA, Je E, Clark DS (2009) Rational shape engineering of the filamentous protein gamma prefoldin through incremental gene truncation. Biopolymers 91:496–503. CrossRefPubMedGoogle Scholar
  38. Yoshida T, Ideno A, Hiyamuta S, Yohda M, Maruyama T (2001) Natural chaperonin of the hyperthermophilic archaeum, Thermococcus strain KS-1: a hetero-oligomeric chaperonin with variable subunit composition. Mol Microbiol 39:1406–1413CrossRefPubMedGoogle Scholar
  39. Zako T et al (2005) Facilitated release of substrate protein from prefoldin by chaperonin. FEBS Lett 579:3718–3724. CrossRefPubMedGoogle Scholar
  40. Zako T et al (2006) Localization of prefoldin interaction sites in the hyperthermophilic group II chaperonin and correlations between binding rate and protein transfer rate. J Mol Biol 364:110–120CrossRefPubMedGoogle Scholar
  41. Zako T, Banba S, Sahlan M, Sakono M, Terada N, Yohda M, Maeda M (2010) Hyperthermophilic archaeal prefoldin shows refolding activity at low temperature. Biochem Biophys Res Commun 391:467–470. CrossRefPubMedGoogle Scholar
  42. Zako T et al (2016) Contribution of the C-terminal region of a group II chaperonin to its interaction with prefoldin and substrate transfer. J Mol Biol 428:2405–2417. CrossRefPubMedGoogle Scholar

Copyright information

© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Muhamad Sahlan
    • 1
    • 2
  • Tamotsu Zako
    • 3
  • Masafumi Yohda
    • 4
    • 5
  1. 1.Department of Chemical EngineeringUniversitas IndonesiaDepokIndonesia
  2. 2.Research Centre for Biomedical Engineering, Faculty of EngineeringUniversitas IndonesiaDepokIndonesia
  3. 3.Department of Chemistry and Biology, Graduate School of Science and EngineeringEhime UniversityMatsuyamaJapan
  4. 4.Department of Biotechnology and Life ScienceTokyo University of Agriculture and TechnologyKoganeiJapan
  5. 5.Institute of Global Innovation ResearchTokyo University of Agriculture and TechnologyKoganeiJapan

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