Logo of biochemjBJ Latest papers and much more!
Biochem J. Jul 15, 1998; 333(Pt 2): 233–242.
PMCID: PMC1219577



The molecular chaperones are a diverse set of protein families required for the correct folding, transport and degradation of other proteins in vivo. There has been great progress in understanding the structure and mechanism of action of the chaperonin family, exemplified by Escherichia coli GroEL. The chaperonins are large, double-ring oligomeric proteins that act as containers for the folding of other protein subunits. Together with its co-protein GroES, GroEL binds non-native polypeptides and facilitates their refolding in an ATP-dependent manner. The action of the ATPase cycle causes the substrate-binding surface of GroEL to alternate in character between hydrophobic (binding/unfolding) and hydrophilic (release/folding). ATP binding initiates a series of dramatic conformational changes that bury the substrate-binding sites, lowering the affinity for non-native polypeptide. In the presence of ATP, GroES binds to GroEL, forming a large chamber that encapsulates substrate proteins for folding. For proteins whose folding is absolutely dependent on the full GroE system, ATP binding (but not hydrolysis) in the encapsulating ring is needed to initiate protein folding. Similarly, ATP binding, but not hydrolysis, in the opposite GroEL ring is needed to release GroES, thus opening the chamber. If the released substrate protein is still not correctly folded, it will go through another round of interaction with GroEL.

Full Text

The Full Text of this article is available as a PDF (587K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Anfinsen CB. Principles that govern the folding of protein chains. Science. 1973 Jul 20;181(4096):223–230. [PubMed]
  • Gething MJ, Sambrook J. Protein folding in the cell. Nature. 1992 Jan 2;355(6355):33–45. [PubMed]
  • Hartl FU. Molecular chaperones in cellular protein folding. Nature. 1996 Jun 13;381(6583):571–579. [PubMed]
  • Ehrnsperger M, Gräber S, Gaestel M, Buchner J. Binding of non-native protein to Hsp25 during heat shock creates a reservoir of folding intermediates for reactivation. EMBO J. 1997 Jan 15;16(2):221–229. [PMC free article] [PubMed]
  • Lee GJ, Roseman AM, Saibil HR, Vierling E. A small heat shock protein stably binds heat-denatured model substrates and can maintain a substrate in a folding-competent state. EMBO J. 1997 Feb 3;16(3):659–671. [PMC free article] [PubMed]
  • Rüdiger S, Buchberger A, Bukau B. Interaction of Hsp70 chaperones with substrates. Nat Struct Biol. 1997 May;4(5):342–349. [PubMed]
  • Flaherty KM, DeLuca-Flaherty C, McKay DB. Three-dimensional structure of the ATPase fragment of a 70K heat-shock cognate protein. Nature. 1990 Aug 16;346(6285):623–628. [PubMed]
  • Zhu X, Zhao X, Burkholder WF, Gragerov A, Ogata CM, Gottesman ME, Hendrickson WA. Structural analysis of substrate binding by the molecular chaperone DnaK. Science. 1996 Jun 14;272(5268):1606–1614. [PubMed]
  • Parsell DA, Kowal AS, Lindquist S. Saccharomyces cerevisiae Hsp104 protein. Purification and characterization of ATP-induced structural changes. J Biol Chem. 1994 Feb 11;269(6):4480–4487. [PubMed]
  • Kessel M, Wu W, Gottesman S, Kocsis E, Steven AC, Maurizi MR. Six-fold rotational symmetry of ClpQ, the E. coli homolog of the 20S proteasome, and its ATP-dependent activator, ClpY. FEBS Lett. 1996 Dec 2;398(2-3):274–278. [PubMed]
  • Chernoff YO, Lindquist SL, Ono B, Inge-Vechtomov SG, Liebman SW. Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [psi+]. Science. 1995 May 12;268(5212):880–884. [PubMed]
  • Stebbins CE, Russo AA, Schneider C, Rosen N, Hartl FU, Pavletich NP. Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent. Cell. 1997 Apr 18;89(2):239–250. [PubMed]
  • Prodromou C, Roe SM, O'Brien R, Ladbury JE, Piper PW, Pearl LH. Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell. 1997 Jul 11;90(1):65–75. [PubMed]
  • Bergeron JJ, Brenner MB, Thomas DY, Williams DB. Calnexin: a membrane-bound chaperone of the endoplasmic reticulum. Trends Biochem Sci. 1994 Mar;19(3):124–128. [PubMed]
  • Freedman RB. The formation of protein disulphide bonds. Curr Opin Struct Biol. 1995 Feb;5(1):85–91. [PubMed]
  • Fedorov AN, Baldwin TO. Cotranslational protein folding. J Biol Chem. 1997 Dec 26;272(52):32715–32718. [PubMed]
  • Baker D, Agard DA. Kinetics versus thermodynamics in protein folding. Biochemistry. 1994 Jun 21;33(24):7505–7509. [PubMed]
  • Jackson GS, Staniforth RA, Halsall DJ, Atkinson T, Holbrook JJ, Clarke AR, Burston SG. Binding and hydrolysis of nucleotides in the chaperonin catalytic cycle: implications for the mechanism of assisted protein folding. Biochemistry. 1993 Mar 16;32(10):2554–2563. [PubMed]
  • Kandror O, Sherman M, Rhode M, Goldberg AL. Trigger factor is involved in GroEL-dependent protein degradation in Escherichia coli and promotes binding of GroEL to unfolded proteins. EMBO J. 1995 Dec 1;14(23):6021–6027. [PMC free article] [PubMed]
  • Tilly K, Murialdo H, Georgopoulos C. Identification of a second Escherichia coli groE gene whose product is necessary for bacteriophage morphogenesis. Proc Natl Acad Sci U S A. 1981 Mar;78(3):1629–1633. [PMC free article] [PubMed]
  • Hemmingsen SM, Woolford C, van der Vies SM, Tilly K, Dennis DT, Georgopoulos CP, Hendrix RW, Ellis RJ. Homologous plant and bacterial proteins chaperone oligomeric protein assembly. Nature. 1988 May 26;333(6171):330–334. [PubMed]
  • Horwich AL, Low KB, Fenton WA, Hirshfield IN, Furtak K. Folding in vivo of bacterial cytoplasmic proteins: role of GroEL. Cell. 1993 Sep 10;74(5):909–917. [PubMed]
  • Ewalt KL, Hendrick JP, Houry WA, Hartl FU. In vivo observation of polypeptide flux through the bacterial chaperonin system. Cell. 1997 Aug 8;90(3):491–500. [PubMed]
  • Fayet O, Ziegelhoffer T, Georgopoulos C. The groES and groEL heat shock gene products of Escherichia coli are essential for bacterial growth at all temperatures. J Bacteriol. 1989 Mar;171(3):1379–1385. [PMC free article] [PubMed]
  • Cheng MY, Hartl FU, Martin J, Pollock RA, Kalousek F, Neupert W, Hallberg EM, Hallberg RL, Horwich AL. Mitochondrial heat-shock protein hsp60 is essential for assembly of proteins imported into yeast mitochondria. Nature. 1989 Feb 16;337(6208):620–625. [PubMed]
  • Klumpp M, Baumeister W, Essen LO. Structure of the substrate binding domain of the thermosome, an archaeal group II chaperonin. Cell. 1997 Oct 17;91(2):263–270. [PubMed]
  • Ditzel L, Löwe J, Stock D, Stetter KO, Huber H, Huber R, Steinbacher S. Crystal structure of the thermosome, the archaeal chaperonin and homolog of CCT. Cell. 1998 Apr 3;93(1):125–138. [PubMed]
  • Kim S, Willison KR, Horwich AL. Cystosolic chaperonin subunits have a conserved ATPase domain but diverged polypeptide-binding domains. Trends Biochem Sci. 1994 Dec;19(12):543–548. [PubMed]
  • Knapp S, Schmidt-Krey I, Hebert H, Bergman T, Jörnvall H, Ladenstein R. The molecular chaperonin TF55 from the Thermophilic archaeon Sulfolobus solfataricus. A biochemical and structural characterization. J Mol Biol. 1994 Sep 30;242(4):397–407. [PubMed]
  • Marco S, Ureña D, Carrascosa JL, Waldmann T, Peters J, Hegerl R, Pfeifer G, Sack-Kongehl H, Baumeister W. The molecular chaperone TF55. Assessment of symmetry. FEBS Lett. 1994 Mar 21;341(2-3):152–155. [PubMed]
  • Löwe J, Stock D, Jap B, Zwickl P, Baumeister W, Huber R. Crystal structure of the 20S proteasome from the archaeon T. acidophilum at 3.4 A resolution. Science. 1995 Apr 28;268(5210):533–539. [PubMed]
  • Groll M, Ditzel L, Löwe J, Stock D, Bochtler M, Bartunik HD, Huber R. Structure of 20S proteasome from yeast at 2.4 A resolution. Nature. 1997 Apr 3;386(6624):463–471. [PubMed]
  • Braig K, Otwinowski Z, Hegde R, Boisvert DC, Joachimiak A, Horwich AL, Sigler PB. The crystal structure of the bacterial chaperonin GroEL at 2.8 A. Nature. 1994 Oct 13;371(6498):578–586. [PubMed]
  • Boisvert DC, Wang J, Otwinowski Z, Horwich AL, Sigler PB. The 2.4 A crystal structure of the bacterial chaperonin GroEL complexed with ATP gamma S. Nat Struct Biol. 1996 Feb;3(2):170–177. [PubMed]
  • Chen S, Roseman AM, Hunter AS, Wood SP, Burston SG, Ranson NA, Clarke AR, Saibil HR. Location of a folding protein and shape changes in GroEL-GroES complexes imaged by cryo-electron microscopy. Nature. 1994 Sep 15;371(6494):261–264. [PubMed]
  • Roseman AM, Chen S, White H, Braig K, Saibil HR. The chaperonin ATPase cycle: mechanism of allosteric switching and movements of substrate-binding domains in GroEL. Cell. 1996 Oct 18;87(2):241–251. [PubMed]
  • Fenton WA, Kashi Y, Furtak K, Horwich AL. Residues in chaperonin GroEL required for polypeptide binding and release. Nature. 1994 Oct 13;371(6498):614–619. [PubMed]
  • Schröder H, Langer T, Hartl FU, Bukau B. DnaK, DnaJ and GrpE form a cellular chaperone machinery capable of repairing heat-induced protein damage. EMBO J. 1993 Nov;12(11):4137–4144. [PMC free article] [PubMed]
  • Todd MJ, Viitanen PV, Lorimer GH. Dynamics of the chaperonin ATPase cycle: implications for facilitated protein folding. Science. 1994 Jul 29;265(5172):659–666. [PubMed]
  • Burston SG, Ranson NA, Clarke AR. The origins and consequences of asymmetry in the chaperonin reaction cycle. J Mol Biol. 1995 May 26;249(1):138–152. [PubMed]
  • Yifrach O, Horovitz A. Nested cooperativity in the ATPase activity of the oligomeric chaperonin GroEL. Biochemistry. 1995 Apr 25;34(16):5303–5308. [PubMed]
  • Gray TE, Fersht AR. Cooperativity in ATP hydrolysis by GroEL is increased by GroES. FEBS Lett. 1991 Nov 4;292(1-2):254–258. [PubMed]
  • Baneyx F, Gatenby AA. A mutation in GroEL interferes with protein folding by reducing the rate of discharge of sequestered polypeptides. J Biol Chem. 1992 Jun 5;267(16):11637–11644. [PubMed]
  • Yifrach O, Horovitz A. Two lines of allosteric communication in the oligomeric chaperonin GroEL are revealed by the single mutation Arg196-->Ala. J Mol Biol. 1994 Oct 28;243(3):397–401. [PubMed]
  • Bochkareva ES, Girshovich AS. ATP induces non-identity of two rings in chaperonin GroEL. J Biol Chem. 1994 Sep 30;269(39):23869–23871. [PubMed]
  • Staniforth RA, Burston SG, Atkinson T, Clarke AR. Affinity of chaperonin-60 for a protein substrate and its modulation by nucleotides and chaperonin-10. Biochem J. 1994 Jun 15;300(Pt 3):651–658. [PMC free article] [PubMed]
  • Yifrach O, Horovitz A. Allosteric control by ATP of non-folded protein binding to GroEL. J Mol Biol. 1996 Jan 26;255(3):356–361. [PubMed]
  • Martin J, Mayhew M, Langer T, Hartl FU. The reaction cycle of GroEL and GroES in chaperonin-assisted protein folding. Nature. 1993 Nov 18;366(6452):228–233. [PubMed]
  • Badcoe IG, Smith CJ, Wood S, Halsall DJ, Holbrook JJ, Lund P, Clarke AR. Binding of a chaperonin to the folding intermediates of lactate dehydrogenase. Biochemistry. 1991 Sep 24;30(38):9195–9200. [PubMed]
  • Staniforth RA, Cortés A, Burston SG, Atkinson T, Holbrook JJ, Clarke AR. The stability and hydrophobicity of cytosolic and mitochondrial malate dehydrogenases and their relation to chaperonin-assisted folding. FEBS Lett. 1994 May 16;344(2-3):129–135. [PubMed]
  • Lilie H, Buchner J. Interaction of GroEL with a highly structured folding intermediate: iterative binding cycles do not involve unfolding. Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8100–8104. [PMC free article] [PubMed]
  • Sparrer H, Lilie H, Buchner J. Dynamics of the GroEL-protein complex: effects of nucleotides and folding mutants. J Mol Biol. 1996 Apr 26;258(1):74–87. [PubMed]
  • Zahn R, Perrett S, Stenberg G, Fersht AR. Catalysis of amide proton exchange by the molecular chaperones GroEL and SecB. Science. 1996 Feb 2;271(5249):642–645. [PubMed]
  • Zahn R, Perrett S, Fersht AR. Conformational states bound by the molecular chaperones GroEL and secB: a hidden unfolding (annealing) activity. J Mol Biol. 1996 Aug 9;261(1):43–61. [PubMed]
  • Landry SJ, Gierasch LM. The chaperonin GroEL binds a polypeptide in an alpha-helical conformation. Biochemistry. 1991 Jul 30;30(30):7359–7362. [PubMed]
  • Schmidt M, Buchner J. Interaction of GroE with an all-beta-protein. J Biol Chem. 1992 Aug 25;267(24):16829–16833. [PubMed]
  • Okazaki A, Ikura T, Nikaido K, Kuwajima K. The chaperonin GroEL does not recognize apo-alpha-lactalbumin in the molten globule state. Nat Struct Biol. 1994 Jul;1(7):439–446. [PubMed]
  • Martin J, Langer T, Boteva R, Schramel A, Horwich AL, Hartl FU. Chaperonin-mediated protein folding at the surface of groEL through a 'molten globule'-like intermediate. Nature. 1991 Jul 4;352(6330):36–42. [PubMed]
  • Hayer-Hartl MK, Ewbank JJ, Creighton TE, Hartl FU. Conformational specificity of the chaperonin GroEL for the compact folding intermediates of alpha-lactalbumin. EMBO J. 1994 Jul 1;13(13):3192–3202. [PMC free article] [PubMed]
  • Buckle AM, Zahn R, Fersht AR. A structural model for GroEL-polypeptide recognition. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3571–3575. [PMC free article] [PubMed]
  • Dessauer CW, Bartlett SG. Identification of a chaperonin binding site in a chloroplast precursor protein. J Biol Chem. 1994 Aug 5;269(31):19766–19776. [PubMed]
  • Fisher MT. The effect of groES on the groEL-dependent assembly of dodecameric glutamine synthetase in the presence of ATP and ADP. J Biol Chem. 1994 May 6;269(18):13629–13636. [PubMed]
  • Mizobata T, Akiyama Y, Ito K, Yumoto N, Kawata Y. Effects of the chaperonin GroE on the refolding of tryptophanase from Escherichia coli. Refolding is enhanced in the presence of ADP. J Biol Chem. 1992 Sep 5;267(25):17773–17779. [PubMed]
  • Walter S, Lorimer GH, Schmid FX. A thermodynamic coupling mechanism for GroEL-mediated unfolding. Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9425–9430. [PMC free article] [PubMed]
  • Weissman JS, Kashi Y, Fenton WA, Horwich AL. GroEL-mediated protein folding proceeds by multiple rounds of binding and release of nonnative forms. Cell. 1994 Aug 26;78(4):693–702. [PubMed]
  • Ranson NA, Dunster NJ, Burston SG, Clarke AR. Chaperonins can catalyse the reversal of early aggregation steps when a protein misfolds. J Mol Biol. 1995 Jul 28;250(5):581–586. [PubMed]
  • White HE, Chen S, Roseman AM, Yifrach O, Horovitz A, Saibil HR. Structural basis of allosteric changes in the GroEL mutant Arg197-->Ala. Nat Struct Biol. 1997 Sep;4(9):690–694. [PubMed]
  • Xu Z, Horwich AL, Sigler PB. The crystal structure of the asymmetric GroEL-GroES-(ADP)7 chaperonin complex. Nature. 1997 Aug 21;388(6644):741–750. [PubMed]
  • Chandrasekhar GN, Tilly K, Woolford C, Hendrix R, Georgopoulos C. Purification and properties of the groES morphogenetic protein of Escherichia coli. J Biol Chem. 1986 Sep 15;261(26):12414–12419. [PubMed]
  • Hunt JF, Weaver AJ, Landry SJ, Gierasch L, Deisenhofer J. The crystal structure of the GroES co-chaperonin at 2.8 A resolution. Nature. 1996 Jan 4;379(6560):37–45. [PubMed]
  • Landry SJ, Zeilstra-Ryalls J, Fayet O, Georgopoulos C, Gierasch LM. Characterization of a functionally important mobile domain of GroES. Nature. 1993 Jul 15;364(6434):255–258. [PubMed]
  • Goloubinoff P, Christeller JT, Gatenby AA, Lorimer GH. Reconstitution of active dimeric ribulose bisphosphate carboxylase from an unfoleded state depends on two chaperonin proteins and Mg-ATP. Nature. 1989 Dec 21;342(6252):884–889. [PubMed]
  • van der Vies SM, Gatenby AA, Georgopoulos C. Bacteriophage T4 encodes a co-chaperonin that can substitute for Escherichia coli GroES in protein folding. Nature. 1994 Apr 14;368(6472):654–656. [PubMed]
  • Hunt JF, van der Vies SM, Henry L, Deisenhofer J. Structural adaptations in the specialized bacteriophage T4 co-chaperonin Gp31 expand the size of the Anfinsen cage. Cell. 1997 Jul 25;90(2):361–371. [PubMed]
  • Weissman JS, Hohl CM, Kovalenko O, Kashi Y, Chen S, Braig K, Saibil HR, Fenton WA, Horwich AL. Mechanism of GroEL action: productive release of polypeptide from a sequestered position under GroES. Cell. 1995 Nov 17;83(4):577–587. [PubMed]
  • Weissman JS, Rye HS, Fenton WA, Beechem JM, Horwich AL. Characterization of the active intermediate of a GroEL-GroES-mediated protein folding reaction. Cell. 1996 Feb 9;84(3):481–490. [PubMed]
  • Mayhew M, da Silva AC, Martin J, Erdjument-Bromage H, Tempst P, Hartl FU. Protein folding in the central cavity of the GroEL-GroES chaperonin complex. Nature. 1996 Feb 1;379(6564):420–426. [PubMed]
  • Burston SG, Weissman JS, Farr GW, Fenton WA, Horwich AL. Release of both native and non-native proteins from a cis-only GroEL ternary complex. Nature. 1996 Sep 5;383(6595):96–99. [PubMed]
  • Ranson NA, Burston SG, Clarke AR. Binding, encapsulation and ejection: substrate dynamics during a chaperonin-assisted folding reaction. J Mol Biol. 1997 Mar 7;266(4):656–664. [PubMed]
  • Rye HS, Burston SG, Fenton WA, Beechem JM, Xu Z, Sigler PB, Horwich AL. Distinct actions of cis and trans ATP within the double ring of the chaperonin GroEL. Nature. 1997 Aug 21;388(6644):792–798. [PubMed]
  • Kad NM, Ranson NA, Cliff MJ, Clarke AR. Asymmetry, commitment and inhibition in the GroE ATPase cycle impose alternating functions on the two GroEL rings. J Mol Biol. 1998 Apr 24;278(1):267–278. [PubMed]
  • Taguchi H, Makino Y, Yoshida M. Monomeric chaperonin-60 and its 50-kDa fragment possess the ability to interact with non-native proteins, to suppress aggregation, and to promote protein folding. J Biol Chem. 1994 Mar 18;269(11):8529–8534. [PubMed]
  • Zahn R, Buckle AM, Perrett S, Johnson CM, Corrales FJ, Golbik R, Fersht AR. Chaperone activity and structure of monomeric polypeptide binding domains of GroEL. Proc Natl Acad Sci U S A. 1996 Dec 24;93(26):15024–15029. [PMC free article] [PubMed]
  • Altamirano MM, Golbik R, Zahn R, Buckle AM, Fersht AR. Refolding chromatography with immobilized mini-chaperones. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3576–3578. [PMC free article] [PubMed]
  • Nicholls A, Sharp KA, Honig B. Protein folding and association: insights from the interfacial and thermodynamic properties of hydrocarbons. Proteins. 1991;11(4):281–296. [PubMed]
  • Esnouf RM. An extensively modified version of MolScript that includes greatly enhanced coloring capabilities. J Mol Graph Model. 1997 Apr;15(2):132–113. [PubMed]
  • Merritt EA, Murphy ME. Raster3D Version 2.0. A program for photorealistic molecular graphics. Acta Crystallogr D Biol Crystallogr. 1994 Nov 1;50(Pt 6):869–873. [PubMed]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


Recent Activity

  • Chaperonins.
    Biochemical Journal. Jul 15, 1998; 333(Pt 2)233

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...