Key Points
-
In the cytosol of prokaryotes and eukaryotes, networks of molecular chaperones can assist polypeptides at all stages of folding.
-
The core chaperone machinery — the 70-kDa heat-shock proteins (Hsp70) and chaperonins — is maintained from prokaryotes to eukaryotes, although the chaperone network is expanded in eukaryotes.
-
To help the folding of nascent polypeptides, the chaperone and peptidyl-prolyl isomerase trigger factor, which is docked on the bacterial ribosome, binds them as they emerge from the ribosomal exit site.
-
Eukaryotic Hsp70 chaperones bind nascent chains as they emerge from ribosomes. In Saccharomyces cerevisiae, the ribosome-associated complex recruits the Ssb Hsp70 chaperones to nascent chains.
-
DnaK, which is the Escherichia coli Hsp70, works together with the chaperonin GroEL to fold newly synthesized proteins; polypeptides can be transferred between these chaperones.
-
In eukaryotes, Hsp70 chaperones can cooperate with the chaperonin TCP1 ring complex (TRiC) to fold newly synthesized polypeptides both during and after their translation (for example, some WD40-repeat proteins).
-
The eukaryotic chaperone GimC/prefoldin can bind nascent chains and work with TRiC to fold actin and tubulin.
-
Some eukaryotic polypeptides are passed from the Hsp70 protein HSC70 (70-kDa heat-shock cognate protein) onto chaperones of the Hsp90 (90-kDa heat-shock protein) family, which can work with several co-chaperones to assist the folding of particular proteins.
-
Co-chaperones of HSC70 and HSP90 are also used to sort polypeptides for mitochondrial targeting or to target them for degradation by the proteasome.
Abstract
Cells are faced with the task of folding thousands of different polypeptides into a wide range of conformations. For many proteins, the folding process requires the action of molecular chaperones. In the cytosol of prokaryotic and eukaryotic cells, molecular chaperones of different structural classes form a network of pathways that can handle substrate polypeptides from the point of initial synthesis on ribosomes to the final stages of folding.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Anfinsen, C. B. Principles that govern the folding of protein chains. Science 181, 223–230 (1973).
Dobson, C. M. & Karplus, M. The fundamentals of protein folding: bringing together theory and experiment. Curr. Opin. Struct. Biol. 9, 92–101 (1999).
Ellis, R. J. Macromolecular crowding: obvious but underappreciated. Trends Biochem. Sci. 26, 597–604 (2001).
Nissen, P., Hansen, J., Ban, N., Moore, P. B. & Steitz, T. A. The structural basis of ribosome activity in peptide bond synthesis. Science 289, 920–930 (2000).
Gilbert, R. J. C. et al. Three-dimensional structures of translating ribosomes by cryo-EM. Mol. Cell 14, 57–66 (2004).
Dobson, C. M. Protein folding and misfolding. Nature 426, 884–890 (2003).
Selkoe, D. J. Folding proteins in fatal ways. Nature 426, 900–904 (2003).
Scholz, C., Stoller, G., Zarnt, T., Fischer, G. & Schmid, F. X. Cooperation of enzymatic and chaperone functions of trigger factor in the catalysis of protein folding. EMBO J. 16, 54–58 (1997).
Valent, Q. A. et al. Nascent membrane and presecretory proteins synthesized in Escherichia coli associate with signal recognition particle and trigger factor. Mol. Microbiol. 25, 53–64 (1997).
Hesterkamp, T., Hauser, S., Lutcke, H. & Bukau, B. Escherichia coli trigger factor is a prolyl isomerase that associates with nascent polypeptide chains. Proc. Natl Acad. Sci. USA 93, 4437–4441 (1996).
Patzelt, H. et al. Binding specificity of Escherichia coli trigger factor. Proc. Natl Acad. Sci. USA 98, 14244–14249 (2001).
Hesterkamp, T., Deuerling, E. & Bukau, B. The amino-terminal 118 amino acids of Escherichia coli trigger factor constitute a domain that is necessary and sufficient for binding to ribosomes. J. Biol. Chem. 272, 21865–21871 (1997).
Kramer, G. et al. L23 protein functions as a chaperone docking site on the ribosome. Nature 419, 171–174 (2002). The nature of the specific interaction between ribosomes and the nascent-chain-binding chaperone TF is determined.
Blaha, G. et al. Localization of the trigger factor binding site on the ribosomal 50S subunit. J. Mol. Biol. 326, 887–897 (2003).
Maier, R., Scholz, C. & Schmid, F. X. Dynamic association of trigger factor with protein substrates. J. Mol. Biol. 314, 1181–1190 (2001).
Genevaux, P. et al. In vivo analysis of the overlapping functions of DnaK and trigger factor. EMBO Rep. 5, 195–200 (2004).
Kramer, G. et al. Trigger factor's peptidyl-prolyl isomerase activity is not essential for the folding of cytosolic proteins in Escherichia coli. J. Biol. Chem. 279, 14165–14170 (2004).
Teter, S. A. et al. Polypeptide flux through bacterial Hsp70: DnaK cooperates with trigger factor in chaperoning nascent chains. Cell 97, 755–765 (1999). Shows that both TF and Hsp70 (DnaK) bind nascent polypeptides and are crucial for the folding of newly synthesized proteins.
Bukau, B. & Horwich, A. L. The Hsp70 and Hsp60 chaperone machines. Cell 92, 351–366 (1998).
Hartl, F. U. & Hayer-Hartl, M. Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295, 1852–1585 (2002).
Hendrick, J. P., Langer, T., Davis, T. A., Hartl, F. U. & Wiedmann, M. Control of folding and membrane translocation by binding of the chaperone DnaJ to nascent polypeptides. Proc. Natl Acad. Sci. USA 90, 10216–10220 (1993).
Deuerling, E., Schulze-Specking, A., Tomoyasu, T., Mogk, A. & Bukau, B. Trigger factor and DnaK cooperate in folding of newly synthesized proteins. Nature 400, 693–696 (1999). Together with reference 18, this report shows a functional cooperation between TF and Hsp70 (DnaK).
Vorderwülbecke, S. et al. Low temperature or GroEL/ES overproduction permits growth of Escherichia coli cells lacking trigger factor and DnaK. FEBS Lett. 559, 181–187 (2004).
Agashe, V. R. et al. Function of trigger factor and DnaK in multi-domain protein folding: increase in yield at the expense of folding speed. Cell 117, 199–209 (2004).
Michimoto, T., Aoki, T., Toh-e, A. & Kikuchi, Y. Yeast Pdr13p and Zuo1p molecular chaperones are new functional Hsp70 and Hsp40 partners. Gene 257, 131–137 (2000).
Gautschi, M. et al. RAC, a stable ribosome-associated complex in yeast formed by the DnaK–DnaJ homologs Ssz1p and zuotin. Proc. Natl Acad. Sci. USA 98, 3762–3767 (2001).
Hundley, H. et al. The in vivo function of the ribosome-associated Hsp70, Ssz1, does not require its putative peptide-binding domain. Proc. Natl Acad. Sci. USA 99, 4203–4208 (2002).
Yan, W. et al. Zuotin, a ribosome-associated DnaJ molecular chaperone. EMBO J. 17, 4809–4817 (1998).
Nelson, R. J., Ziegelhoffer, T., Nicolet, C., Werner-Washburne, M. & Craig, E. A. The translation machinery and 70 kD heat shock protein cooperate in protein synthesis. Cell 71, 97–105 (1992). Presents some of the earliest evidence for a functional cooperation of cytosolic chaperones with the translation machinery.
Pfund, C. et al. The molecular chaperone Ssb from Saccharomyces cerevisiae is a component of the ribosome–nascent chain complex. EMBO J. 17, 3981–3989 (1998).
Siegers, K. et al. TRiC/CCT cooperates with different upstream chaperones in the folding of distinct protein classes. EMBO J. 22, 5230–5240 (2003). Shows that the chaperonin TRiC works with two types of chaperone, Hsp70 (Ssb) and GimC, to fold subsets of its substrates.
Gautschi, M., Mun, A., Ross, S. & Rospert, S. A functional chaperone triad on the yeast ribosome. Proc. Natl Acad. Sci. USA 99, 4209–4214 (2002).
Beckmann, R. P., Mizzen, L. E. & Welch, W. J. Interaction of Hsp70 with newly synthesized proteins: implications for protein folding and assembly. Science 248, 850–854 (1990).
Frydman, J., Nimmesgern, E., Ohtsuka, K. & Hartl, F. U. Folding of nascent polypeptide chains in a high molecular mass assembly with molecular chaperones. Nature 370, 111–117 (1994).
Eggers, D. K., Welch, W. J. & Hansen, W. J. Complexes between nascent polypeptides and their molecular chaperones in the cytosol of mammalian cells. Mol. Biol. Cell 8, 1559–1573 (1997).
Terada, K., Kanazawa, M., Bukau, B. & Mori, M. The human DnaJ homologue dj2 facilitates mitochondrial protein import and luciferase refolding. J. Cell Biol. 139, 1089–1095 (1997).
Nagata, H., Hansen, W. J., Freeman, B. & Welch, W. J. Mammalian cytosolic DnaJ homologues affect the hsp70 chaperone–substrate reaction cycle, but do not interact directly with nascent or newly synthesized proteins. Biochemistry 37, 6924–6938 (1998).
McCallum, C. D., Do, H., Johnson, A. E. & Frydman, J. The interaction of the chaperonin tailless complex polypeptide 1 (TCP1) ring complex (TRiC) with ribosome-bound nascent chains examined using photo-crosslinking. J. Cell Biol. 149, 591–602 (2000). The results in this paper indicate a tight coupling between translation and chaperone-assisted protein folding.
Wiedmann, B., Sakai, H., Davis, T. A. & Wiedmann, M. A protein complex required for signal-sequence-specific sorting and translocation. Nature 370, 434–440 (1994).
Shi, X., Parthun, M. R. & Jaehning, J. A. The yeast EGD2 gene encodes a homologue of the α-NAC subunit of the human nascent-polypeptide-associated complex. Gene 165, 199–202 (1995).
Horwich, A. L., Low, K. B., Fenton, W. A., Hirshfield, I. N. & Furtak, K. Folding in vivo of bacterial cytoplasmic proteins: role of GroEL. Cell 74, 909–917 (1993).
Ewalt, K. L., Hendrick, J. P., Houry, W. A. & Hartl, F. U. In vivo observation of polypeptide flux through the bacterial chaperonin system. Cell 90, 491–500 (1997).
Langer, T. et al. Successive action of DnaK, DnaJ and GroEL along the pathway of chaperone-mediated protein folding. Nature 356, 683–689 (1992). This early paper shows that Hsp70 (DnaK) and chaperonins cooperate mechanistically in polypeptide folding.
Houry, W. A., Frishman, D., Eckerskorn, D., Lottspeich, F. & Hartl, F. U. Identification of in vivo substrates of the chaperonin GroEL. Nature 402, 147–154 (1999).
Buchberger, A., Schröder, H., Hesterkamp, T., Schönfeld, H. J. & Bukau, B. Substrate shuttling between the DnaK and GroEL systems indicates a chaperone network promoting protein folding. J. Mol. Biol. 261, 328–333 (1996).
Segal, G. & Ron, E. Z. Regulation of the heat-shock response in bacteria. Ann. NY Acad. Sci. 851, 147–151 (1998).
Hesterkamp, T. & Bukau, B. Role of the DnaK and HscA homologs of Hsp70 chaperones in protein folding in E. coli. EMBO J. 17, 4818–4828 (1998).
Chaudhuri, T. K., Farr, G. W., Fenton, W. A., Rospert, S. & Horwich, A. L. GroEL/GroES-mediated folding of a protein too large to be encapsulated. Cell 107, 235–246 (2001). A new mechanism for bacterial GroEL/ES is described, in which the substrate is bound only by the open end of the chaperonin system. This raises the possibility of GroEL interactions with nascent chains.
Valpuesta, J. M, Mart'n-Benito, J., Gómez-Puertas, P., Carrascosa, J. L. & Willison, K. R. Structure and function of a protein folding machine: the eukaryotic chaperonin CCT. FEBS Lett. 529, 11–16 (2002).
Llorca, O. et al. The 'sequential allosteric ring' mechanism in the eukaryotic chaperonin-assisted folding of actin and tubulin. EMBO J. 20, 4065–4075 (2001).
Klumpp, M., Baumeister, W. & Essen, L. -O. Structure of the substrate binding domain of the thermosome, an archaeal group II chaperonin. Cell 91, 263–270 (1997).
Ditzel, L. et al. Crystal structure of the thermosome, the archaeal chaperonin and homolog of CCT. Cell 93, 125–138 (1998).
Meyer, A. S. et al. Closing the folding chamber of the eukaryotic chaperonin requires the transition state of ATP hydrolysis. Cell 113, 369–381 (2003). The eukaryotic chaperonin TRiC is shown to use an encapsulation mechanism to assist the folding of its substrates, which is conceptually similar to the mechanism that is used by the bacterial chaperonin system GroEL–GroES.
Gao, Y., Thomas, J. O., Chow, R. L., Lee, G. H. & Cowan, N. J. A cytoplasmic chaperonin that catalyzes β-actin folding. Cell 69, 1043–1050 (1992).
Yaffe, M. B. et al. TCP1 complex is a molecular chaperone in tubulin biogenesis. Nature 358, 245–248 (1992).
Farr, G. W., Scharl, E. C., Schumacher, R. J., Sondek, S. & Horwich, A. L. Chaperonin-mediated folding in the eukaryotic cytosol proceeds through rounds of release of native and nonnative forms. Cell 89, 927–937 (1997).
Won, K. A., Schumacher, R. J., Farr, G. W., Horwich, A. L. & Reed, S. I. Maturation of human cyclin E requires the function of eukaryotic chaperonin CCT. Mol. Cell. Biol. 18, 7584–7589 (1998).
Feldman, D. E., Thulasiraman, V., Ferreyra, R. G. & Frydman, J. Formation of the VHL–elongin BC tumor suppressor complex is mediated by the chaperonin TRiC. Mol. Cell 4, 1051–1061 (1999).
Camasses, A., Bogdanova, A., Shevchenko, A. & Zachariae, W. The CCT chaperonin promotes activation of the anaphase-promoting complex through the generation of functional Cdc20. Mol. Cell 12, 87–100 (2003).
Kim, S., Schilke, B., Craig, E. A. & Horwich, A. L. Folding in vivo of a newly translated yeast cytosolic enzyme is mediated by the SSA class of cytosolic yeast Hsp70 proteins. Proc. Natl Acad. Sci. USA 95, 12860–12865 (1998).
Johnson, J. L. & Craig, E. A. An essential role for the substrate-binding region of Hsp40s in Saccharomyces cerevisiae. J. Cell Biol. 152, 851–856 (2001).
Melville, M. W., McClellan, A. J., Meyer, A. S., Darveau, A. & Frydman, J. The Hsp70 and TRiC/CCT chaperone systems cooperate in vivo to assemble the von Hippel–Lindau tumor suppressor complex. Mol. Cell. Biol. 23, 3141–3151 (2003).
Geissler, S., Siegers, K. & Schiebel, E. A novel protein complex promoting formation of functional α- and γ-tubulin. EMBO J. 17, 952–966 (1998).
Vainberg, I. E. et al. Prefoldin, a chaperone that delivers unfolded proteins to cytosolic chaperonin. Cell 93, 863–873 (1998).
Siegert, R., Leroux, M. R., Scheufler, C., Hartl, F. U. & Moarefi, I. Structure of the molecular chaperone prefoldin: unique interaction of multiple coiled coil tentacles with unfolded proteins. Cell 103, 621–632 (2000).
Mart'n-Benito, J. et al. Structure of eukaryotic prefoldin and of its complexes with unfolded actin and the cytosolic chaperonin CCT. EMBO J. 21, 6377–6386 (2002).
Hansen, W. J., Cowan, N. J. & Welch, W. J. Prefoldin–nascent chain complexes in the folding of cytoskeletal proteins. J. Cell Biol. 145, 265–277 (1999).
Siegers, K. et al. Compartmentation of protein folding in vivo: sequestration of non-native polypeptide by the chaperonin–GimC system. EMBO J. 18, 75–84 (1999).
Simons, C. T. et al. Selective contribution of eukaryotic prefoldin subunits to actin and tubulin binding. J. Biol. Chem. 179, 4196–4203 (2004).
Llorca, O. et al. Eukaryotic type II chaperonin CCT interacts with actin through specific subunits. Nature 402, 693–696 (1999).
Llorca, O. et al. Eukaryotic chaperonin CCT stabilizes actin and tubulin folding intermediates in open quasi-native conformations. EMBO J. 19, 5971–5979 (2000).
Young, J. C., Moarefi, I. & Hartl, F. U. Hsp90: a specialized but essential protein folding tool. J. Cell Biol. 154, 267–273 (2001).
Richter, K. & Buchner, J. Hsp90: chaperoning signal transduction. J. Cell. Phys. 188, 281–290 (2001).
Pratt, W. B. & Toft, D. O. Regulation of signalling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Exp. Biol. Med. 228, 111–133 (2003).
Panaretou, B. et al. ATP binding and hydrolysis are essential to the function of the Hsp90 molecular chaperone in vivo. EMBO J. 17, 4829–4836 (1998).
Young, J. C. & Hartl, F. U. Polypeptide release by Hsp90 involves ATP hydrolysis and is enhanced by the co-chaperone p23. EMBO J. 19, 5930–5940 (2000).
Sangster, T. A., Lindquist, S. & Queitsch, C. Under cover: causes, effects and implications of Hsp90-mediated genetic capacitance. BioEssays 26, 348–362 (2004).
Hernandez, M. P., Chadli, A. & Toft, D. O. HSP40 is the first step in the HSP90 chaperoning pathway for the progesterone receptor. J. Biol. Chem. 277, 11873–11881 (2002).
Riggs, D. L. et al. The Hsp90-binding peptidylprolyl isomerase FKBP52 potentiates glucocorticoid signaling in vivo. EMBO J. 22, 1158–1167 (2003).
Stepanova, L., Leng, X., Parker, S. B. & Harper, J. W. Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilized Cdk4. Genes Dev. 10, 1491–1502 (1996).
Dey, B., Lightbody, J. J. & Boschelli, F. CDC37 is required for p60v-src activity in yeast. Mol. Biol. Cell 7, 1405–1417 (1996).
Dai, K., Kobayashi, R. & Beach, D. Physical interaction of mammalian CDC37 with CDK4. J. Biol. Chem. 271, 22030–22034 (1996).
Chen, G., Cao, P. & Goeddel, D. V. TNF-induced recruitment and activation of the IKK complex requires Cdc37 and Hsp90. Mol. Cell 9, 401–410 (2002).
Basso, A. D. et al. Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. J. Biol. Chem. 277, 39858–39866 (2002).
Lange, B. M., Rebollo, E., Herold, A. & González, C. Cdc37 is essential for chromosome segregation and cytokinesis in higher eukaryotes. EMBO J. 21, 5364–5374 (2002).
Tatebe, H. & Shiozaki, K. Identification of Cdc37 as a novel regulator of the stress-responsive mitogen-activated protein kinase. Mol. Cell. Biol. 23, 5132–5142 (2003).
Hartson, S. D. et al. p50cdc37 is a nonexclusive Hsp90 cohort which participates intimately in Hsp90-mediated folding of immature kinase molecules. Biochemistry 39, 7631–7644 (2000).
Lee, P. et al. The Cdc37 protein kinase-binding domain is sufficient for protein kinase activity and cell viability. J. Cell Biol. 159, 1051–1059 (2002).
Lee, P., Shabbir, A., Cardozo, C. & Caplan, A. J. Sti1 and Cdc37 can stabilize Hsp90 in chaperone complexes with a protein kinase. Mol. Biol. Cell 15, 1785–1792 (2004).
Kazlauskas, A., Sundstrom, S., Poellinger, L. & Pongratz, I. The hsp90 chaperone complex regulates intracellular localization of the dioxin receptor. Mol. Cell. Biol. 21, 2594–2607 (2001).
Lees, M. J., Peet, D. J. & Whitelaw, M. L. Defining the role for XAP2 in stabilization of the dioxin receptor. J. Biol. Chem. 278, 35878–35888 (2003).
Barral, J. M., Hutagalung, A. H., Brinker, A., Hartl, F. U. & Epstein, H. F. Role of the myosin assembly protein UNC-45 as a molecular chaperone for myosin. Science 295, 669–671 (2002).
Takahashi, A., Casais, C., Ichimura, K. & Shirasu, K. HSP90 interacts with RAR1 and SGT1 and is essential for RPS2-mediated disease resistance in Arabidopsis. Proc. Natl Acad. Sci. USA 100, 11777–11782 (2003).
Hubert, D. A. et al. Cytosolic HSP90 associates with and modulates the Arabidopsis RPM1 disease resistance protein. EMBO J. 22, 5679–5689 (2003).
Lu, R. et al. High throughput virus-induced gene silencing implicates heat shock protein 90 in plant disease resistance. EMBO J. 22, 5690–5699 (2003).
Liu, Y., Burch-Smith, T., Schiff, M., Feng, S. & Dinesh-Kumar, S. P. Molecular chaperone Hsp90 associates with resistance protein N and its signaling proteins SGT1 and RAR1 to modulate an innate immune response in plants. J. Biol. Chem. 279, 2101–2108 (2004).
Kitagawa, K., Skowyra, D., Elledge, S. J., Harper, J. W. & Hieter, P. SGT1 encodes an essential component of the yeast kinetochore assembly pathway and a novel subunit of the SCF ubiquitin ligase complex. Mol. Cell 4, 21–33 (1999).
Stemmann, O., Neidig, A., Köcher, T., Wilm, M. & Lechner, J. Hsp90 enables Ctf13p/Skp1p to nucleate the budding yeast kinetochore. Proc. Natl Acad. Sci. USA 99, 8585–8590 (2002).
Kamal, A. et al. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425, 407–410 (2003). Shows that HSP90 in complexes in tumour cells is much more active than in untransformed cells, in which it is largely uncomplexed. This increased activity involves interactions with Hsp70 (HSC70) and co-chaperones of both HSP90 and HSC70.
Höhfeld, J., Cyr, D. M. & Patterson, C. From the cradle to the grave: molecular chaperones that may choose between folding and degradation. EMBO Rep. 2, 885–890 (2001).
Cyr, D. M., Höhfeld, J. & Patterson, C. Protein quality control: U-box-containing E3 ubiquitin ligases join the fold. Trends Biochem. Sci. 27, 368–375 (2002).
Young, J. C., Barral, J. M. & Hartl, F. U. More than folding: localized functions of cytosolic chaperones. Trends Biochem. Sci. 28, 541–547 (2003).
Truscott, K. N., Brandner, K. & Pfanner, N. Mechanisms of protein import into mitochondria. Curr. Biol. 13, R326–R337 (2003).
Deshaies, R. J., Koch, B. C., Werner-Washburne, M., Craig, E. A. & Schekman, R. W. A subfamily of stress proteins facilitates translocation of secretory and mitochondrial precursor polypeptides. Nature 332, 800–805 (1988).
Terada, K. et al. The requirement of heat shock cognate 70 protein for mitochondrial import varies among precursor proteins and depends on precursor length. Mol. Cell. Biol. 16, 6103–6109 (1996).
Young, J. C., Hoogenraad, N. J. & Hartl, F. U. Molecular chaperones Hsp90 and Hsp70 deliver preproteins to the mitochondrial import receptor Tom70. Cell 112, 41–50 (2003). Reports the discovery of a specific interaction that directs the HSC70–HSP90 chaperone machinery to the mitochondrial outer membrane for the purpose of protein targeting.
Yano, M., Terada, K. & Mori, M. AIP is a mitochondrial import mediator that binds to both import receptor Tom20 and preproteins. J. Cell Biol. 163, 45–56 (2003).
Becker, J., Walter, W., Yan, W. & Craig, E. A. Functional interaction of cytosolic hsp70 and a DnaJ related protein, Ydj1p, in protein translocation in vivo. Mol. Cell. Biol. 16, 4378–4386 (1996).
Glickman, M. H. & Ciechanover, A. The ubiquitin–proteasome proteolytic pathway: destruction for the sake of construction. Physiol. Rev. 82, 373–428 (2002).
Takayama, S. & Reed, J. C. Molecular chaperone targeting and regulation by BAG family proteins. Nature Cell Biol. 3, E237–E241 (2001).
Höhfeld, J. & Jentsch, S. GrpE-like regulation of the Hsc70 chaperone by the anti-apoptotic protein BAG-1. EMBO J. 16, 6209–6216 (1997).
Sondermann, H. et al. Structure of a Bag/Hsc70 complex: convergent functional evolution of Hsp70 nucleotide exchange factors. Science 291, 1553–1557 (2001).
Connell, P. et al. Regulation of heat shock protein-mediated protein triage decisions by the co-chaperone CHIP. Nature Cell Biol. 3, 93–96 (2001).
Meacham, G. C., Patterson, C., Zhang, W., Younger, J. M. & Cyr, D. The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation. Nature Cell Biol. 3, 100–105 (2001). References 113 and 114 show that the HSC70 and HSP90 chaperones are linked to the ubiquitin-mediated proteasome-degradation system through a ubiquitin-ligase co-chaperone. This indicates that these chaperones function in protein quality control.
Demand, J., Alberti, S., Patterson, C. & Höhfeld, J. Cooperation of a ubiquitin domain protein and an E3 ubiquitin ligase during chaperone/proteasome coupling. Curr. Biol. 11, 1569–1577 (2002).
Alberti, S. et al. Ubiquitylation of BAG-1 suggests a novel regulatory mechanism during the sorting of chaperone substrates to the proteasome. J. Biol. Chem. 277, 45920–45927 (2002).
Song, J., Takeda, M. & Morimoto, R. I. Bag1–Hsp70 mediates a physiological stress signalling pathway that regulates Raf-1/ERK and cell growth. Nature Cell Biol. 3, 276–282 (2001).
Dai, Q. et al. CHIP activates HSF1 and confers protection against apoptosis and cellular stress. EMBO J. 22, 5446–5458 (2003).
Thomas, J. G. & Baneyx, F. ClpB and HtpG facilitate de novo protein folding in stressed Escherichia coli cells. Mol. Microbiol. 36, 1360–1370 (2000).
Borkovich, K. A., Farrelly, F. W., Finkelstein, D. B., Taulien, J. & Lindquist, S. Hsp82 is an essential protein that is required in higher concentrations for growth of cells at higher temperature. Mol. Cell. Biol. 9, 3919–3930 (1989).
Yue, L. et al. Genetic analysis of viable Hsp90 alleles reveals a critical role in Drosophila spermatogenesis. Genetics 151, 1065–1079 (1999).
Wang, J. D., Herman, C., Tipton, K. A., Gross, C. A. & Weissman, J. S. Directed evolution of substrate-optimized GroEL/S chaperonins. Cell 111, 1027–1039 (2002).
Mogk, A. & Bukau, B. Molecular chaperones: structure of a protein disaggregase. Curr. Biol. 14, R78–R80 (2004).
Mogk, A. et al. Identification of thermolabile Escherichia coli proteins: prevention and reversion of aggregation by DnaK and ClpB. EMBO J. 18, 6934–6949 (1999).
Glover, J. R. & Lindquist, S. Hsp104, Hsp70, and Hsp40: a novel chaperone system that rescues previously aggregated proteins. Cell 94, 73–82 (1998).
Schlee, S., Beinker, P., Akhrymuk, A. & Reinstein, J. A chaperone network for the resolubilization of protein aggregates: direct interaction of ClpB and DnaK. J. Mol. Biol. 336, 275–285 (2004).
Freeman, B. C. & Yamamoto, K. R. Disassembly of transcriptional regulatory complexes by molecular chaperones. Science 296, 2232–2235 (2002).
Rutherford, S. L. & Lindquist, S. Hsp90 as a capacitor for morphological evolution. Nature 396, 336–342 (1998). Proposes a role for HSP90 in buffering widespread genetic variation in morphogenic pathways and, therefore, in potentiating evolutionary change through the occasional selection of an accumulated variation.
Ferbitz, L. et al. Trigger factor in complex with the ribosome forms a molecular cradle for nascent proteins. Nature 29 Aug 2004 (doi:10.1038/nature02899).
Lopez-Buesa, P., Pfund, C. & Craig, E. A. The biochemical properties of the ATPase activity of a 70-kDa heat shock protein (Hsp70) are governed by the C-terminal domains. Proc. Natl Acad. Sci. USA 95, 15253–15258 (1998).
Kabani, M., McLellan, C., Raynes, D. A., Guerriero, V. & Brodsky, J. L. HspBP1, a homologue of the yeast Fes1 and Sls1 proteins, is an Hsc70 nucleotide exchange factor. FEBS Lett. 531, 339–342 (2002).
Kabani, M., Beckerich, J. -M. & Brodsky, J. L. Nucleotide exchange factor for the yeast Hsp70 molecular chaperone Ssa1p. Mol. Cell. Biol. 22, 4677–4689 (2002).
Höhfeld, J., Minami, Y. & Hartl, F. U. Hip, a novel cochaperone involved in the eukaryotic Hsc70/Hsp40 cycle. Cell 83, 589–598 (1995).
Nollen, E. A. A. et al. Modulation of in vivo Hsp70 chaperone activity by Hip and Bag-1. J. Biol. Chem. 276, 4677–4682 (2001).
Hallstrom, T. C., Katzmann, D. J., Torres, R. J., Sharp, W. J. & Moye-Rowley, W. S. Regulation of transcription factor Pdr1p function by an Hsp70 protein in Saccharomyces cerevisiae. Mol. Cell. Biol. 18, 1147–1155 (1998).
Ullers, R. S. et al. SecB is a bona fide generalized chaperone in Escherichia coli. Proc. Natl Acad. Sci. USA 101, 7583–7588 (2004).
Pearl, L. H. & Prodromou, C. Structure, function and mechanism of the Hsp90 molecular chaperone. Adv. Protein Chem. 59, 157–186 (2001).
Scheufler, C. et al. Structure of TPR domain–peptide complexes: critical elements in the assembly of the Hsp70–Hsp90 multichaperone machine. Cell 101, 199–210 (2000).
Prodromou, C. et al. Regulation of Hsp90 ATPase activity by tetratricopeptide repeat (TPR)-domain co-chaperones. EMBO J. 18, 754–762 (1999).
Brychzy, A. et al. Cofactor Tpr2 combines two TPR domains and a J domain to regulate the Hsp70/Hsp90 chaperone system. EMBO J. 22, 3613–3623 (2003).
Panaretou, B. et al. Activation of the ATPase of hsp90 by the stress-regulated cochaperone Aha1. Mol. Cell 10, 1307–1318 (2002).
Lotz, G. P., Lin, H., Harst, A. & Obermann, W. M. Aha1 binds to the middle domain of Hsp90, contributes to client protein activation, and stimulates the ATPase of the molecular chaperone. J. Biol. Chem. 278, 17228–17235 (2003).
Roe, S. M. et al. The mechanism of Hsp90 regulation by the protein kinase-specific cochaperone p50cdc37. Cell 116, 87–98 (2004).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
Related links
DATABASES
Swiss-Prot
FURTHER INFORMATION
Max-Planck-Institute for Biochemistry: Department for Cellular Biochemistry
Glossary
- MOLECULAR CHAPERONES
-
Proteins that help the folding of other proteins, usually through cycles of binding and release, without forming part of their final native structure.
- EXCLUDED VOLUME EFFECT
-
Extremely high concentrations of inert macromolecules are thought to affect the thermodynamics of reactions between other macromolecules by reducing the available volume in the solution. This effect is observed as an increase in the rates and affinities of intermolecular binding reactions.
- TERTIARY STRUCTURE
-
This term refers to the native three-dimensional conformation of a polypeptide, in which secondary (local) structure elements are packed against each other and specific contacts can form between sections of a polypeptide chain that are widely separated in the amino-acid sequence.
- PEPTIDYL-PROLYL CIS–TRANS ISOMERASE
-
The folding of some proteins requires the rotation of a peptide bond that precedes a proline residue from the trans (extended) to the cis (bent) position, which normally takes place slowly. The peptidyl-prolyl isomerases catalyse this interconversion, which can increase the folding rate of some proteins.
- CHAPERONINS
-
A family of chaperone proteins that have a characteristic double-ring structure. One class of chaperonin, which functions with a capping cofactor, is found in bacteria (for example, GroEL of Escherichia coli), and in the interior of mitochondria and chloroplasts. A second class of chaperonin, which functions without a capping cofactor, is found in the cytosol of eukaryotes (for example, TCP1-ring complex (TRiC)) and in archaea (thermosomes).
- IMMUNOPHILINS
-
A family of intracellular eukaryotic proteins that contain a structurally related peptidyl-prolyl cis–trans isomerase domain and bind immunosuppressive drugs, such as FK506 (rapamycin).
- J DOMAIN
-
A conserved domain that stimulates ATP hydrolysis by chaperones of the 70-kDa heat-shock protein (Hsp70) family. It was first identified in the Escherichia coli co-chaperone DnaJ, but it is also found in DnaJ homologues in eukaryotes, as well as in several co-chaperones that recruit Hsp70 proteins for specific cellular processes.
- WD40 REPEAT
-
A poorly conserved repeat sequence of 40–60 amino acids, which usually ends with Trp-Asp (WD). Several consecutive repeats fold into a circular structure, a so-called β-propeller, in which each blade is a four-stranded β-sheet. This domain is found in proteins that have various different functions.
- TETRATRICOPEPTIDE REPEAT-CLAMP DOMAIN
-
(TPR-clamp domain). TPR motifs are 34-amino-acid degenerate repeat sequences. Some eukaryotic co-chaperones of the cytosolic 70- and 90-kDa heat-shock proteins (HSC70 and HSP90, respectively) contain specialized TPR-clamp domains, which consist of three TPR motifs and 'clamp' a conserved aspartate residue at the carboxyl termini of HSC70 and HSP90.
- SARCOMERE
-
A specialized structure in striated muscle, in which actin filaments contact numerous molecules of myosin, the motor protein that makes up muscle thick filaments. The movement of actin and myosin filaments past each other provides the driving force for muscle contraction.
- KINETOCHORES
-
Specialized regions on chromosomes that are connected to microtubules and motor proteins during cell division in eukaryotes. Kinetochores function in the separation of chromosome pairs.
- SKP1–CULLIN–F-BOX UBIQUITIN-LIGASE COMPLEX
-
A conserved protein complex in eukaryotes that is named on the basis of three of its characteristic components. It transfers ubiquitin onto specific substrate proteins and polyubiquitylated proteins are targeted for proteasomal degradation. It functions in the regulated degradation of proteins and is also essential for cell division.
- U-BOX-TYPE E3 UBIQUITIN LIGASE
-
A class of ubiquitin-ligase domain that can transfer ubiquitin onto substrate proteins. It was first identified in the Ufd2 protein of Saccharomyces cerevisiae, and has since been found in several proteins from both yeast and mammals.
- AAA PROTEINS
-
'ATPases associated with various cellular activities'. A superfamily of structurally related proteins (usually hexameric), a subset of which function to unfold proteins and a related subset of which function as proteases.
- CAPACITOR OF MORPHOLOGY
-
The 90-kDa heat-shock protein (HSP90) has been proposed to buffer cryptic genetic variability by allowing mutated regulatory proteins to function normally. Phenotypes or morphologies that are associated with these mutations are only observed under stress conditions, when HSP90 function is reduced or overloaded, and favourable phenotypes can then be selected in a heritable manner. This mechanism is referred to as genetic capacitance.
Rights and permissions
About this article
Cite this article
Young, J., Agashe, V., Siegers, K. et al. Pathways of chaperone-mediated protein folding in the cytosol. Nat Rev Mol Cell Biol 5, 781–791 (2004). https://doi.org/10.1038/nrm1492
Issue Date:
DOI: https://doi.org/10.1038/nrm1492
This article is cited by
-
Upregulation of Hsp27 via further inhibition of histone H2A ubiquitination confers protection against myocardial ischemia/reperfusion injury by promoting glycolysis and enhancing mitochondrial function
Cell Death Discovery (2023)
-
Introducing Molecular Chaperones into the Causality and Prospective Management of Autoimmune Hepatitis
Digestive Diseases and Sciences (2023)
-
Incorporating the Molecular Mimicry of Environmental Antigens into the Causality of Autoimmune Hepatitis
Digestive Diseases and Sciences (2023)
-
Functional implication of heat shock protein 70/90 and tubulin in cold stress of Dermacentor silvarum
Parasites & Vectors (2021)
-
In Silico Analysis of HSP70 Gene Family in Bovine Genome
Biochemical Genetics (2021)