Abstract
Protein destabilization by mutations or external stresses may lead to misfolding and aggregation in the cell. Often, damage is not limited to a simple loss of function, but the hydrophobic exposure of aggregate surfaces may impair membrane functions and promote the aggregation of other proteins. Such a “proteinacious infectious” behavior is not limited to prion diseases. It is associated to most protein-misfolding neurodegenerative diseases and to aging in general. With the molecular chaperones and proteases, cells have evolved powerful tools that can specifically recognize and act upon misfolded and aggregated proteins. Whereas some chaperones passively prevent aggregate formation and propagation, others actively unfold and solubilize stable aggregates. In particular, ATPase chaperones and proteases serve as an intracellular defense network that can specifically identify and actively remove by refolding or degradation potentially infectious cytotoxic aggregates. Here we discuss two types of molecular mechanisms by which ATPase chaperones may actively solubilize stable aggregates: (1) unfolding by power strokes, using the Hsp100 ring chaperones, and (2) unfolding by random movements of individual Hsp70 molecules. In bacteria, fungi, and plants, the two mechanisms are key for reducing protein damages from abiotic stresses. In animals devoid of Hsp100, Hsp70 appears as the core element of the chaperone network, preventing the formation and actively removing disease-causing protein aggregates.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Anfinsen, C.B. (1973). Principles that govern the folding of protein chains. Science 181:223–230.
Benaroudj, N., and Goldberg, A.L. (2000). PAN, the proteasome-activating nucleotidase from archaebacteria, is a proteinunfolding molecular chaperone. Nat. Cell Biol. 2:833–839.
Ben-Zvi, A.P., and Goloubinoff, P. (2001). Review: mechanisms of disaggregation and refolding of stable protein aggregates by molecular chaperones. J. Struct. Biol. 135:84–93.
Ben-Zvi, A.P., and Goloubinoff, P. (2002). Proteinaceous infectious behavior in non-pathogenic proteins is controlled by molecular chaperones. J. Biol. Chem. 277:49422–49427.
Ben-Zvi, A.P., Chatellier, J., Fersht, A.R., and Goloubinoff, P. (1998). Minimal and optimal mechanisms for GroE-mediated protein folding. Proc. Natl. Acad. Sci. USA 95:15275–15280.
Ben-Zvi A., De Los Rios, P., Dietler, G., and Goloubinoff, P. (2004). Active solubilization and refolding of stable protein aggregates by cooperative unfolding action of individual HSP70 chaperones. J. Biol. Chem. 279:37298–37303.
Buchner, J., Schmidt, M., Fuchs, M., Jaenicke, R., Rudolph, R., Schmid, F.X., and Kiefhaber, T. (1991). GroE facilitates refolding of citrate synthase by suppressing aggregation. Biochemistry 30:1586–1591.
Corsi, A.K., and Schekman, R. (1997). The lumenal domain of Sec63p stimulates the ATPase activity of BiP and mediates BiP recruitment to the translocon in Saccharomyces cerevisiae. J. Cell Biol. 137:1483–1493.
Cyr, M.D. (1995). Cooperation of the molecular chaperone Ydj1 with specific Hsp70 homologs to suppress protein aggregation. FEBS Lett. 359:129–132.
Deuerling, E., Schulze-Specking, A., Tomoyasu, T., Mogk, A., and Bukau, B. (1999). Trigger factor and DnaK cooperate in folding of newly synthesized proteins. Nature 400:693–696.
Diamant, S., and Goloubinoff, P. (1998). Temperature-controlled activity of DnaK-DnaJ-GrpE chaperones: protein-folding arrest and recovery during and after heat shock depends on the substrate protein and the GrpE concentration. Biochemistry 37:9688–9694.
Diamant, S., Ben-Zvi, A.P., Bukau, B., and Goloubinoff, P. (2000). Size-dependent disaggregation of stable protein aggregates by the DnaK chaperone machinery. J. Biol. Chem. 275:21107–21113.
Diamant, S., Eliahu, N., Rosenthal, D., and Goloubinoff, P. (2001). Chemical chaperones regulate molecular chaperones in vitro and in cells under combined salt and heat stresses. J. Biol. Chem. 276:39586–39591.
Diamant, S., Rosenthal, D., Azem, A., Eliahu, N., Ben-Zvi, A.P., and Goloubinoff, P. (2003). Dicarboxylic amino acids and glycine-betaine regulate chaperone-mediated protein-disaggregation under stress. Mol. Microbiol. 49:401–410.
Ellis, R.J. (2000). Chaperone substrates inside the cell. Trends Biochem. Sci. 25:210–212.
Ellis, R.J. (2001). Molecular chaperones: inside and outside the Anfinsen cage. Curr. Biol. 11:R1038–R1040.
Fandrich, M., and Dobson, C.M. (2002). The behaviour of polyamino acids reveals an inverse side chain effect in amyloid structure formation. EMBO J. 21:5682–5690.
Farr, G.W., Furtak, K., Rowland, M.B., Ranson, N.A., Saibil, H.R., Kirchhausen, T., and Horwich, A.L. (2000). Multivalent binding of nonnative substrate proteins by the chaperonin GroEL. Cell 100:561–573.
Forreiter, C., Kirschner, M., and Nover, L. (1997). Stable transformation of an Arabidopsis cell suspension culture with firefly luciferase providing a cellular system for analysis of chaperone activity in vivo. Plant Cell. 9:2171–2181.
Frydman, J. (2001). Folding of newly translated proteins in vivo: the role of molecular chaperones. Annu. Rev. Biochem. 70:603–647.
Glover, J.R., and Lindquist, S. (1998). Hsp104, Hsp70, and Hsp40: a novel chaperone system that rescues previously aggregated proteins. Cell 94:73–82.
Goloubinoff, P., Christeller, J.T., Gatenby, A.A., and Lorimer, G.H. (1989a). Reconstitution of active dimeric ribulose bisphosphate carboxylase from an unfolded state depends on two chaperonin proteins and Mg-ATP. Nature 342:884–889.
Goloubinoff, P., Gatenby, A.A., and Lorimer, G.H. (1989b). GroE heat-shock proteins promote assembly of foreign prokaryotic ribulose bisphosphate carboxylase oligomers in Escherichia coli. Nature 337:44–47.
Goloubinoff, P., Mogk, A., Ben-Zvi, A.P., Tomoyasu, T., and Bukau, B. (1999). Sequential mechanism of solubilization and refolding of stable protein aggregates by a bichaperone network. Proc. Natl. Acad. Sci. USA 96:13732–13737.
Harrison, C.J., Hayer-Hartl, M., Di Liberto, M., Hartl, F., and Kuriyan, J. (1997). Crystal structure of the nucleotide exchange factor GrpE bound to the ATPase domain of the molecular chaperone DnaK. Science 276:431–435.
Hartl, F.U., and Hayer-Hartl, M. (2002). Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295:1852–1858.
Holl, N.B., Rudolph, R., Schmidt, M., and Buchner, J. (1991). Reconstitution of a heat shock effect in vitro: influence of GroE on the thermal aggregation of alpha-glucosidase from yeast. Biochemistry 30:11609–11614.
Horst, M., Azem, A., Schatz, G., and Glick, B.S. (1997). What is the driving force for protein import into mitochondria? Biochim. Biophys. Acta 1318:71–78.
Horwitz, J. (1992). Alpha-crystallin can function as a molecular chaperone. Proc. Natl. Acad. Sci. U A 89:10449–10453.
Hoskins, J.R., Singh, S.K., Maurizi, M.R., and Wickner, S. (2000). Protein binding and unfolding by the chaperone ClpA and degradation by the protease ClpAP. Proc. Natl. Acad. Sci. USA 97:8892–8897.
Jaenicke, R. (1995). Folding and association versus misfolding and aggregation of proteins. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 348:97–105.
Jana, N.R., and Nukina, N. (2003). Recent advances in understanding the pathogenesis of polyglutamine diseases: involvement of molecular chaperones and ubiquitin-proteasome pathway. J. Chem. Neuroanat. 26:95–101.
Jana, N.R., Tanaka, M., Wang, G., and Nukina, N. (2000). Polyglutamine length-dependent interaction of Hsp40 and Hsp70 family chaperones with truncated N-terminal huntingtin: their role in suppression of aggregation and cellular toxicity. Hum. Mol. Genet. 9:2009–2018.
Jaroniec, C.P., MacPhee, C.E., Astrof, N.S., Dobson, C.M., and Griffin, R.G. (2002). Molecular conformation of a peptide fragment of transthyretin in an amyloid fibril. Proc. Natl. Acad. Sci. USA 99:16748–16753.
Kim, Y.I., Burton, R.E., Burton, B.M., Sauer, R.T., and Baker, T.A. (2000). Dynamics of substrate denaturation and translocation by the ClpXP degradation machine. Mol. Cell 5:639–648.
Kopito, R.R. (2000). Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol. 10:524–530.
Lee, S., Sowa, M.E., Watanabe, Y.H., Sigler, P.B., Chiu, W., Yoshida, M., and Tsai, F.T. (2003). The structure of ClpB: a molecular chaperone that rescues proteins from an aggregated state. Cell 115:229–240.
Martin, J., and Hartl, F.-U. (1997). The effect of macromolecular crowding on chaperonin-mediated protein folding. Proc. Natl. Acad. Sci. USA 94:1107–1112.
Martin-Aparicio, E., Yamamoto, A., Hernandez, F., Hen, R., Avila, J., and Lucas, J.J. (2001). Proteasomal-dependent aggregate reversal and absence of cell death in a conditional mouse model of Huntington’s disease. J. Neurosci. 21:8772–8781.
Matouschek, A., Azem, A., Ratliff, K., Glick, B.S., Schmid, K., and Schatz, G. (1997). Active unfolding of precursor proteins during mitochondrial protein import. EMBO J. 16:6727–6736.
Mogk, A., and Bukau, B. (2004). Molecular chaperones: structure of a protein disaggregase. Curr. Biol. 14:R78–R80.
Mogk, A., Tomoyasu, T., Goloubinoff, P., Rudiger, S., Roder, D., Langen, H., and Bukau, B. (1999). Identification of thermolabile Escherichia coli proteins: prevention and reversion of aggregation by DnaK and ClpB. EMBO J. 18:6934–6949.
Navon, A., and Goldberg, A.L. (2001). Proteins are unfolded on the surface of the ATPase ring before transport into the proteasome. Mol. Cell 8:1339–1349.
Neupert, W., and Brunner, M. (2002). The protein import motor of mitochondria. Nat. Rev. Mol. Cell. Biol. 3:555–565.
Nielsen, E., Akita, M., Davila-Aponte, J., and Keegstra, K. (1997). Stable association of chloroplastic precursors with protein translocation complexes that contain proteins from both envelope membranes and a stromal Hsp100 molecular chaperone. EMBO J. 16:935–946.
Parsell, D.A., Kowal, A.S., Singer, M.A., and Lindquist, S. (1994). Protein disaggregation mediated by heat-shock protein Hsp104. Nature 372:475–478.
Perutz, M.F., Finch, J.T., Berriman, J., and Lesk, A. (2002). Amyloid fibers are water-filled nanotubes. Proc. Natl. Acad. Sci. USA 99:5591–5595.
Roseman, A.M., Chen, S., White, H., Braig, K., and Saibil, H.R. (1996). The chaperonin ATPase cycle: mechanism of allosteric switching and movements of substrate-binding domains in GroEL. Cell 87:241–251.
Rouiller, I., DeLaBarre, B., May, A.P., Weis, W.I., Brunger, A.T., Milligan, R.A., and Wilson-Kubalek, E.M. (2002). Conformational changes of the multifunction p97 AAA ATPase during its ATPase cycle. Nat. Struct. Biol. 9:950–957.
Rudiger, S., Buchberger, A., and Bukau, B. (1997). Interaction of Hsp70 chaperones with substrates. Nat. Struct. Biol. 4:342–349.
Sakahira, H., Breuer, P., Hayer-Hartl, M.K., and Hartl, F.U. (2002). Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity. Proc. Natl. Acad. Sci. USA 99:16412–16418.
Schaffitzel, E., Rudiger, S., Bukau, B., and Deuerling, E. (2001). Functional dissection of trigger factor and DnaK: interactions with nascent polypeptides and thermally denatured proteins. Biol. Chem. 382:1235–1243.
Schliwa, M., and Woehlke, G. (2003). Molecular motors. Nature 422:759–765.
Schönfeld, H.-J., Schmidt, D., Schröder, H., and Bukau, B. (1995). The DnaK chaperone system of Escherichia coli: quaternary structures and interactions of the DnaK and GrpE components. J. Biol. Chem. 270:2183–2189.
Schröder, H., Langer, T., Hartl, F.-U., and Bukau, B. (1993). DnaK, DnaJ, GrpE form a cellular chaperone machinery capable of repairing heat-induced protein damage. EMBO J. 12:4137–4144.
Shtilerman, M., Lorimer, G.H., and Englander, S.W. (1999). Chaperonin function: folding by forced unfolding. Science 284:822–825.
Singh, S.K., Grimaud, R., Hoskins, J.R., Wickner, S., and Maurizi, M.R. (2000). Unfolding and internalization of proteins by the ATP-dependent proteases ClpXP and ClpAP. Proc. Natl. Acad. Sci. USA 97:8898–8903.
Skowyra, D., Georgopoulos, C., and Zylicz, M. (1990). The E. coli dnaK gene product, the hsp70 homolog, can reactivate heat-inactivated RNA polymerase in an ATP hydrolysis-dependent manner. Cell 62:939–944.
Slepenkov, S.V., and Witt, S.N. (2002). The unfolding story of the Escherichia coli Hsp70 DnaK: is DnaK a holdase or an unfoldase? Mol. Microbiol. 45:1197–1206.
Tomoyasu, T., Mogk, A., Langen, H., Goloubinoff, P., and Bukau, B. (2001). Genetic dissection of the roles of chaperones and proteases in protein folding and degradation in the Escherichia coli cytosol. Mol. Microbiol. 40:397–413.
van den Berg, B., Ellis, R.J., and Dobson, C.M. (1999). Effects of macromolecular crowding on protein folding and aggregation. EMBO J. 18:6927–6933.
Veinger, L., Diamant, S., Buchner, J., and Goloubinoff, P. (1998). The small heat-shock protein IbpB from Escherichia coli stabilizes stress-denatured proteins for subsequent refolding by a multichaperone network. J. Biol. Chem. 273:11032–11037.
Viitanen, P.V., Lubben, T.H., Reed, J., Goloubinoff, P., O’Keefe, D.P., and Lorimer, G.H. (1990). Chaperonin-facilitated refolding of ribulosebisphosphate carboxylase and ATP hydrolysis by chaperonin 60 (groEL) are K+ dependent. Biochemistry 29:5665–5671.
Walter, S., Lorimer, G.H., and Schmid, F.X. (1996). A thermodynamic coupling mechanism for GroEL-mediated unfolding. Proc. Natl. Acad. Sci. USA 93:9425–9430.
Watanabe, Y.H., and Yoshida, M. (2004). Trigonal DnaK-DnaJ complex vs free DnaK and DnaJ; heat stress converts the former to the latter and only the latter can do disaggregation in cooperation with ClpB. J. Biol. Chem. 279:15723–15727.
Weber-Ban, E.U., Reid, B.G., Miranker, A.D., and Horwich, A.L. (1999). Global unfolding of a substrate protein by the Hsp100 chaperone ClpA. Nature 401:90–93.
Weibezahn, J., Tessarz, P., Schlieker, C., Zahn, R., Maglica, Z., Lee, S., Zentgraf, H., Weber-Ban, E.U., Dougan, D.A., Tsai, F.T., Mogk, A., and Bukau, B. (2004) Thermotolerance requires refolding of aggregated proteins by substrate translocation through the central pore of ClpB. Cell 119:653–665.
Weissman, J.S., Hohl, C.M., Kovalenko, O., Kashi, Y., Chen, S., Braig, K., Saibil, H.R., Fenton, W.A., and Horwich, A.L. (1995). Mechanism of GroEL action: productive release of polypeptide from a sequestered position under GroES. Cell 83:577–587.
Wiech, H., Buchner, J., Zimmermann, R., and Jakob, U. (1992). Hsp90 chaperones protein folding in vitro. Nature 358:169–170.
Xu, Z., Horwich, A.L., and Sigler, P.B. (1997). The crystal structure of the asymmetric GroEL-GroES-(ADP)7 chaperonin complex. Nature 388:741–750.
Yamamoto, A., Lucas, J.J., and Hen, R. (2000). Reversal of neuropathology and motor dysfunction in a conditional model of Huntington’s disease. Cell 101:57–66.
Zahn, R., Buckle, A.M., Perrett, S., Johnson, C.M., Corrales, F.J., Golbik, R., and Fersht, A.R. (1996a). Chaperone activity and structure of monomeric polypeptide binding domains of GroEL. Proc. Natl. Acad. Sci. USA 93:15024–15029.
Zahn, R., Perrett, S., and Fersht, A.R. (1996b). Conformational states bound by the molecular chaperones GroEL and secB: a hidden unfolding (annealing) activity. J. Mol. Biol. 261:43–61.
Zhang, X., Beuron, F., and Freemont, P.S. (2002). Machinery of protein folding and unfolding. Curr. Opin. Struct. Biol. 12:231–238.
Zhu, M., Li, J., and Fink, A.L. (2003). The association of alpha-synuclein with membranes affects bilayer structure, stability, and fibril formation. J. Biol. Chem. 278:40186–40197.
Zhu, X., Zhao, X., Burkholder, W.F., Gragerov, A., Ogata, C.M., Gottesman, M.E., and Hendrickson, W.A. (1996). Structural analysis of substrate binding by the molecular chaperone DnaK. Science 272:1606–1614.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2006 Springer Science+Business Media, Inc.
About this chapter
Cite this chapter
Goloubinoff, P., Ben-Zvi, A.P. (2006). Mechanisms of Active Solubilization of Stable Protein Aggregates by Molecular Chaperones. In: Uversky, V.N., Fink, A.L. (eds) Protein Misfolding, Aggregation, and Conformational Diseases. Protein Reviews, vol 4. Springer, Boston, MA. https://doi.org/10.1007/0-387-25919-8_9
Download citation
DOI: https://doi.org/10.1007/0-387-25919-8_9
Publisher Name: Springer, Boston, MA
Print ISBN: 978-0-387-25918-5
Online ISBN: 978-0-387-25919-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)