Prefoldins in Archaea

  • Samuel Lim
  • Dominic J. Glover
  • Douglas S. ClarkEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1106)


Molecular chaperones promote the correct folding of proteins in aggregation-prone cellular environments by stabilizing nascent polypeptide chains and providing appropriate folding conditions. Prefoldins (PFDs) are molecular chaperones found in archaea and eukaryotes, generally characterized by a unique jellyfish-like hexameric structure consisting of a rigid beta-barrel backbone with protruding flexible coiled-coils. Unlike eukaryotic PFDs that mainly interact with cytoskeletal components, archaeal PFDs can stabilize a wide range of substrates; such versatility reflects PFD’s role as a key element in archaeal chaperone systems, which often lack general nascent-chain binding chaperone components such as Hsp70. While archaeal PFDs mainly exist as hexameric complexes, their structural diversity ranges from tetramers to filamentous oligomers. PFDs bind and stabilize nonnative proteins using varying numbers of coiled-coils, and subsequently transfer the substrate to a group II chaperonin (CPN) for refolding. The distinct structure and specific function of archaeal PFDs have been exploited for a broad range of applications in biotechnology; furthermore, a filament-forming variant of PFD has been used to fabricate nanoscale architectures of defined shapes, demonstrating archaeal PFDs’ potential applicability in nanotechnology.


Prefoldin Chaperone Archaea Thermostability Self-assembly Protein folding Aggregation Chaperonin Coiled-coil Nanotechnology 



This work was supported by the Air Force Office of Scientific Research (FA9550-17-1-0451). S.L. was supported by a National Science Foundation Graduate Research Fellowship (DGE1106400, DGE1752814).


  1. Baek AH, Jeon EY, Lee SM, Park JB (2014) Expression levels of chaperones influence biotransformation activity of recombinant Escherichia coli expressing Micrococcus luteus alcohol dehydrogenase and Pseudomonas putida Baeyer–Villiger monooxygenase. Biotechnol Bioeng 112:889–895CrossRefGoogle Scholar
  2. Balchin D, Hayer-Hartl M, Hartl FU (2016) In vivo aspects of protein folding and quality control. Science 353:aac4354CrossRefGoogle Scholar
  3. Bando K, Zako T, Sakono M, Maeda M, Wada T, Nishijima M, Fukuhara G, Yang C, Mori T, Pace TCS, Bohne C, Inoue Y (2010) Bio-supramolecular photochirogenesis with molecular chaperone: enantiodifferentiating photocyclodimerization of 2-anthracenecarboxylatemediated by prefoldin. Photochem Photobiol Sci 9:655–660CrossRefGoogle Scholar
  4. Boonyaratanakornkit BB, Simpson AJ, Whitehead TA, Fraser CM, El-Sayed NMA, Clark DS (2005) Transcriptional profiling of the hyperthermophilic methanarchaeon Methanococcus jannaschii in response to lethal heat and non-lethal cold shock. Environ Microbiol 7:789–797CrossRefGoogle Scholar
  5. Chen H, Yang L, Zhang Y, Yang S (2010) Over-expression and characterization of recombinant prefoldin from hyperthermophilic archaeum Pyrococcus furiosus in E. coli. Biotechnol Lett 32:429–434CrossRefGoogle Scholar
  6. Danno A, Fukuda W, Yoshida M, Aki R, Tanaka T, Kanai T, Imanaka T, Fujiwara S (2008) Expression profiles and physiological roles of two types of prefoldins from the hyperthermophilic archaeon Thermococcus kodakaraensis. J Mol Biol 382:298–311CrossRefGoogle Scholar
  7. Douglas NR, Reissmann S, Zhang J, Chen B, Jakana J, Kumar R, Chiu W, Frydman J (2011) Dual action of ATP hydrolysis couples lid closure to substrate release into the group II chaperonin chamber. Cell 144:240–252CrossRefGoogle Scholar
  8. Fandrich M, Tito MA, Leroux MR, Rostom AA, Hartl FU, Dobson CM, Robinson CV (2000) Observation of the noncovalent assembly and disassembly pathways of the chaperone complex MtGimC by mass spectrometry. Proc Natl Acad Sci U S A 97:14151–14155CrossRefGoogle Scholar
  9. Fukui T, Atomi H, Kanai T, Matsumi R, Fujiwara S, Imanaka T (2005) Complete genome sequence of the hyperthermophilic archaeon Thermococcus kodakaraensis KOD1 and comparison with Pyrococcus genomes. Genome Res 15:352–363CrossRefGoogle Scholar
  10. Geissler S, Siegers K, Schiebel E (1998) A novel protein complex promoting formation of functional alpha- and gamma-tubulin. EMBO J 17:955–966CrossRefGoogle Scholar
  11. Ghaffari A, Shokuhfar A, Ghasemi RH (2012) Capturing and releasing a nano cargo by Prefoldin nano actuator. Sensors Actuators B Chem 171–172:1199–1206CrossRefGoogle Scholar
  12. Glover DJ, Clark DS (2015) Oligomeric assembly is required for chaperone activity of the filamentous γ-prefoldin. FEBS J 282:2985–2997CrossRefGoogle Scholar
  13. Glover DJ, Clark DS (2016) Protein calligraphy: a new concept begins to take shape. ACS Cent Sci 2:438–444CrossRefGoogle Scholar
  14. Glover DJ, Giger L, Kim JR, Clark DS (2012) Engineering protein filaments with enhanced thermostability for nanomaterials. Biotechnol J 8:228–236CrossRefGoogle Scholar
  15. Glover DJ, Giger L, Kim SS, Naik RR, Clark DS (2016) Geometrical assembly of ultrastable protein templates for nanomaterials. Nat Commun 7:11771CrossRefGoogle Scholar
  16. Goloubinoff P, Gatenby AA, Lorimer GH (1989) GroE heat-shock proteins promote assembly of foreign prokaryotic ribulose bisphosphate carboxylase oligomers in Escherichia coli. Nature 337:44–47CrossRefGoogle Scholar
  17. Hartl FU, Hayer-Hartl M (2002) Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295:1852–1858CrossRefGoogle Scholar
  18. Iizuka R, Sugano Y, Ide N, Ohtaki A, Yoshida T, Fujiwara S, Imanaka T, Yohda M (2008) Functional characterization of recombinant prefoldin complexes from a hyperthermophilic archaeon, Thermococcus sp. strain KS-1. J Mol Biol 377:972–983CrossRefGoogle Scholar
  19. Kida H, Sugano Y, Iizuka R, Fujihashi M, Yohda M, Miki K (2008) Structural and molecular characterization of the prefoldin β subunit from Thermococcus strain KS-1. J Mol Biol 383:465–474CrossRefGoogle Scholar
  20. Laksanalamai P, Whitehead TA, Robb FT (2004) Minimal protein-folding systems in hyperthermophilic archaea. Nat Rev Microbiol 2:315–324CrossRefGoogle Scholar
  21. Leroux MR (2001) Protein folding and molecular chaperones in archaea. Adv Appl Microbiol 50:219–277CrossRefGoogle Scholar
  22. Leroux MR, Fandrich M, Klunker D, Siegers K, Lupas AN, Brown JR, Schiebel E, Dobson CM, Hartl FU (1999) MtGimC, a novel archaeal chaperone related to the eukaryotic chaperonin cofactor GimC/prefoldin. EMBO J 18:6730–6743CrossRefGoogle Scholar
  23. 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 101:4367–4372CrossRefGoogle Scholar
  24. Martin-Benito J, Boskovic J, Gomez-Puertas P, Carrascosa JL, Simons CT, Lewis SA, Bartolini F, Cowan NJ, Valpuesta JM (2002) Structure of eukaryotic prefoldin and of its complexes with unfolded actin and the cytosolic chaperonin CCT. EMBO J 21:6377–6386CrossRefGoogle Scholar
  25. Martin-Benito J, Gomez-Reino J, Stirling PC, Lundin VF, Gomez-Puertas P, Boskovic J, Chacon P, Fernandez JJ, Berenguer J, Leroux MR, Valpuesta JM (2007) Divergent substrate-binding mechanisms reveal an evolutionary specialization of eukaryotic prefoldin compared to its archaeal counterpart. Structure 15:101–110CrossRefGoogle Scholar
  26. Nishihara K, Kanemori M, Yanagi H, Yura T (2000) Overexpression of trigger factor prevents aggregation of recombinant proteins in Escherichia coli. Appl Environ Microbiol 66:884–889CrossRefGoogle Scholar
  27. Ohtaki A, Kida H, Miyata Y, Ide N, Yonezawa A, Arakawa T, Iizuka R, Noguchi K, Kita A, Odaka M, Miki K, Yohda M (2008) Structure and molecular dynamics simulation of archaeal prefoldin: the molecular mechanism for binding and recognition of nonnative substrate proteins. J Mol Biol 376:1130–1141CrossRefGoogle Scholar
  28. Ohtaki A, Noguchi K, Yohda M (2010) Structure and function of archaeal prefoldin, a co-chaperone of group II chaperonin. Front Biosci 15:108–117CrossRefGoogle Scholar
  29. Okochi M, Nomura T, Zako T, Arakawa T, Iizuka R, Ueda H, Funatsu T, Leroux M, Yohda M (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 279:31788–31795CrossRefGoogle Scholar
  30. Okochi M, Kanie K, Kurimoto M, Yohda M, Honda H (2008) Overexpression of prefoldin from the hyperthermophilic archaeum Pyrococcus horikoshii OT3 endowed Escherichia coli with organic solvent tolerance. Appl Microbiol Biotechnol 79:443–449CrossRefGoogle Scholar
  31. Peng S, Chu Z, Lu J, Li D, Wang Y, Yang S, Zhang Y (2016) Co-expression of chaperones from P. furiosus enhanced the soluble expression of the recombinant hyperthermophilic α-amylase in E. coli. Cell Stress Chaperones 21:477–484CrossRefGoogle Scholar
  32. Peng SY, Chu ZM, Lu JF, Li DX, Wang YH, Yang SL, Zhang Y (2017) Co-expression of Prefoldin from Hyperthermophilic archaea Pyrococcus furiosus in Escherichia coli enhances the catalytic efficiency of modified cytochrome P450 BM3. Prog Biochem Biophys 44:1125–1131Google Scholar
  33. Sahlan M, Yohda M (2013) Molecular chaperones in thermophilic eubacteria and archaea. In: Satyanarayana T et al (eds) Thermophilic microbes in environmental and industrial biotechnology: biotechnology of thermophiles, vol 2E. Springer, Dordrecht, pp 375–394CrossRefGoogle Scholar
  34. Sahlan M, Zako T, Tai PT, Ohtaki A, Noguchi K, Maeda M, Miyatake H, Dohmae N, Yohda M (2010) Thermodynamic characterization of the interaction between prefoldin and group II chaperonin. J Mol Biol 399:628–636CrossRefGoogle Scholar
  35. Sahlan M, Zako T, Yohda M (2018) Prefoldin, a jellyfish-like molecular chaperone: functional cooperation with a group II chaperonin and beyond. Biophys Rev 10:339–345. CrossRefPubMedPubMedCentralGoogle Scholar
  36. Sakono M, Zako T, Drakulic S, Valpuesta JM, Yohda M, Maeda M (2010) Size-selective recognition of gold nanoparticles by a molecular chaperone. Chem Phys Lett 501:108–112CrossRefGoogle Scholar
  37. Sakono M, Zako T, Yohda M, Maeda M (2012) Amyloid oligomer detection by immobilized molecular chaperone. Biochem Eng J 61:28–33CrossRefGoogle Scholar
  38. Shockley KR, Ward DE, Chhabra SR, Conners SB, Montero CI, Kelly RM (2003) Heat shock response by the hyperthermophilic archaeon Pyrococcus furiosus. Appl Environ Microbiol 69:2365–2371CrossRefGoogle Scholar
  39. Shokuhfar A, Ghaffari A, Ghasemi RH (2012) Cavity control of Prefoldin nano actuator (PNA) by temperature and pH. Nano-Micro Lett 4:110–117CrossRefGoogle Scholar
  40. Siegert R, Leroux MR, Scheufler C, Hartl FU, Moarefi I (2000) Structure of the molecular chaperone prefoldin: unque interaction of multiple coiled coil tentacles with unfolded proteins. Cell 103:621–632CrossRefGoogle Scholar
  41. 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 279:4196–4203CrossRefGoogle Scholar
  42. Slocik JM, Kim SN, Whitehead TA, Clark DS, Naik RR (2009) Biotemplated metal nanowires using hyperthermophilic protein filaments. Small 5:2038–2042CrossRefGoogle Scholar
  43. 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 93:863–873CrossRefGoogle Scholar
  44. Wall JG, Pluckthun A (1995) Effects of overexpressing folding modulators on the in vivo folding of heterologous proteins in Escherichia coli. Curr Opin Biotechnol 6:507–516CrossRefGoogle Scholar
  45. 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 16:626–634CrossRefGoogle Scholar
  46. Whitehead TA, Meadows AL, Clark DS (2008) Controlling the self-assembly of a filamentous hyperthermophilic chaperone by an engineered capping protein. Small 4:956–960CrossRefGoogle Scholar
  47. Whitehead TA, Je E, Clark DS (2009) Rational shape engineering of the filamentous protein gamma prefoldin through incremental gene truncation. Biopolymers 91:496–503CrossRefGoogle Scholar
  48. Yan X, Hu S, Guan YX, Yao SJ (2012) Coexpression of chaperonin GroEL/GroES markedly enhanced soluble and functional expression of recombinant human interferon-gamma in Escherichia coli. Appl Microbiol Biotechnol 93:1065–1074CrossRefGoogle Scholar
  49. Zako T, Maeda M (2014) Application of biomaterials for the detection of amyloid aggregates. Biomater Sci 2:951–955CrossRefGoogle Scholar
  50. Zako T, Iizuka R, Okochi M, Nomura T, Ueno T, Tadakuma H, Yohda M, Funatsu T (2005) Facilitated release of substrate protein from prefoldin by chaperonin. FEBS Lett 579:3718–3724CrossRefGoogle Scholar
  51. Zako T, Murase Y, Iizuka R, Yoshida T, Kanzaki T, Ide N, Maeda M, Funatsu T, Yohda M (2006) Localization of prefoldin interaction sites in the hyperthermophilic group II chaperonin and correlations between binding rate and protein transfer rate. J Mol Biol 364:110–120CrossRefGoogle Scholar
  52. Zhang J, Baker ML, Schroder GF, Douglas NR, Reissmann S, Jakana J, Dougherty M, Fu CJ, Levitt M, Ludtke SJ, Frydman J, Chiu W (2010) Mechanism of folding chamber closure in a group II chaperonin. Nature 463:379–383CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Samuel Lim
    • 1
  • Dominic J. Glover
    • 2
  • Douglas S. Clark
    • 1
    Email author
  1. 1.Department of Chemical and Biological EngineeringUniversity of CaliforniaBerkeleyUSA
  2. 2.School of Biotechnology and Biomolecular SciencesUniversity of New South WalesSydneyAustralia

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