Abstract
The generic tendency of proteins to aggregate into non-functional, and sometimes cytotoxic, structures poses a universal problem for all types of cell. This tendency is greatly exacerbated by the high total concentration of macromolecules found within most intracellular compartments, a phenomenon referred to as macromolecular crowding. This review discusses the quantitative effects of crowding on protein aggregation and the role of molecular chaperones in combating this problem.
References
Acampora, G. and Hermans, J. Jr. (1966). Reversible denaturation of sperm whale myoglobin I. Dependence on temperature, pH and composition. J. Am. Chem. Soc.89, 1543–1547.Search in Google Scholar
Anfinsen, C.B. (1973). Principles that govern the folding of protein chains. Science181, 231–230.10.1126/science.181.4096.223Search in Google Scholar
Atha, D.H. and Ingham, K.C. (1981). Mechanism of precipitation of proteins by polyethylene glycol. Analysis in terms of excluded volume. J. Biol. Chem.256, 12108–12117.Search in Google Scholar
Betancourt, M.R. and Thirumalai, D. (1999). Exploring the kinetic requirements for enhancement of protein folding rates in the GroEL cavity. J. Mol. Biol.287, 627–644.10.1006/jmbi.1999.2591Search in Google Scholar
Betts, S., Haase-Pettingell, C., and King, J. (1997). Mutational effects on inclusion body formation. Adv. Protein Chem.50, 243–264.10.1016/S0065-3233(08)60323-XSearch in Google Scholar
Boublík, T. (1974). Statistical thermodynamics of convex molecule fluids. Mol. Phys.27, 1415–1427.10.1080/00268977400101191Search in Google Scholar
Brinker, A., Pfeifer, G., Kerner, M.J., Naylor, D.J., Hartl, F.U., and Hayer-Hartl, M. (2001). Dual function of protein confinement in chaperonin-assisted protein folding. Cell107, 223–233.10.1016/S0092-8674(01)00517-7Search in Google Scholar
Chargé, S.B.P., de Koning, E.J.P., and Clark, A. (1995). Effects of pH and insulin on fibrillogenesis of islet amyloid polypeptide in vitro. Biochemistry34, 14588–14593.10.1021/bi00044a038Search in Google Scholar
Cotter, M.A. (1977). Hard spherocylinder in an anisotropic mean field: a simple model for a nematic liquid crystal. J. Chem. Phys.66, 1098–1106.10.1063/1.434044Search in Google Scholar
Crick, F.H.C. (1958). On protein synthesis. Symp. Soc. Exp. Biol.13, 138–163.Search in Google Scholar
Cuneo, P., Magri, E., Verzola, A., and Grazi, E. (1992). ‘Macromolecular crowding’ is a primary factor in the organization of the cytoskeleton. Biochem. J.281, 507–512.10.1042/bj2810507Search in Google Scholar
Dinner, A.R., Sali, A., Smith, L.J., Dobson, C.M., and Karplus, M. (2000). Understanding protein folding via free-energy surfaces from theory and experiment. Trends Biochem. Sci.25, 331–339.10.1016/S0968-0004(00)01610-8Search in Google Scholar
Dobson, C.M. (2001). The structural basis for protein folding and its links with human disease. Phil. Trans. R. Soc. B356, 133–145.10.1098/rstb.2000.0758Search in Google Scholar PubMed PubMed Central
Dobson, C.M., Ellis, R.J., and Fersht, A.R. (2001). Protein misfolding and disease. Phil. Trans. R. Soc. B356, 127–227.Search in Google Scholar
Drenckhahn, D. and Pollard, T.D. (1986). Elongation of actin filaments is a diffusion-limited reaction at the barbed end and is accelerated by inert macromolecules. J. Biol. Chem.261, 12754–12758.10.1016/S0021-9258(18)67157-1Search in Google Scholar
Eaton, W.A. and Hofrichter, J. (1990). Sickle cell hemoglobin polymerization. Adv. Protein Chem.40, 63–279.10.1016/S0065-3233(08)60287-9Search in Google Scholar
Ellis, R.J. (2001). Macromolecular crowding: obvious but under-appreciated. Trends Biochem. Sci.26, 597–604.10.1016/S0968-0004(01)01938-7Search in Google Scholar
Ellis, R.J. (2003). Protein folding: importance of the Anfinsen cage. Curr. Biol.13, R881–R883.10.1016/j.cub.2003.10.051Search in Google Scholar
Ellis, R.J. and Hemmingsen, S.M. (1989). Molecular chaperones: proteins essential for the biogenesis of some macromolecular structures. Trends Biochem. Sci.14, 339–342.10.1016/0968-0004(89)90168-0Search in Google Scholar
Epstein, C.J., Goldberger, R.F., and Anfinsen, C.B. (1963). The genetic control of tertiary protein structure: studies with model systems. Cold Spring Harbor Symp. Quant. Biol.28, 439–449.10.1101/SQB.1963.028.01.060Search in Google Scholar
Ferrone, F.A. and Rotter, M.A. (2004). Crowding and the polymerization of sickle hemoglobin. J. Mol. Recognit.17, 497–504.10.1002/jmr.698Search in Google Scholar
Fulton, A.B. (1982). How crowded is the cytoplasm? Cell30, 345–347.10.1016/0092-8674(82)90231-8Search in Google Scholar
Giddings, J.C., Kucera, E., Russell, C.P., and Myers, N.M. (1968). Statistical theory for the equilibrium distribution of rigid molecules in inert porous networks. Exclusion chromatography. J. Phys. Chem.72, 4397–4408.Search in Google Scholar
Goldberg, M.E., Rudolph, R., and Jaenicke, R. (1991). A kinetic study of the competition between renaturation and aggregation during refolding of denatured reduced egg white lysozyme. Biochemistry30, 2790–2797.10.1021/bi00225a008Search in Google Scholar PubMed
Gonzalez, J., Jimenez, M., Velez, M., Mingorance, J., Andreu, J.M., Vicente, M., and Rivas, G. (2003). Essential cell division protein FtsZ assembles into one-monomer-thick ribbons under conditions resembling the crowded intracellular environment. J. Biol. Chem.278, 37664–37671.10.1074/jbc.M305230200Search in Google Scholar PubMed
Hall, D. and Minton, A.P. (2002). Effects of inert volume-excluding macromolecules on protein fiber formation. I. Equilibrium models. Biophys. Chem.98, 93–104.Search in Google Scholar
Hall, D. and Minton, A.P. (2004). Effects of inert volume-excluding macromolecules on protein fiber formation.II. Kinetic models for nucleated fiber growth. Biophys. Chem.107, 299–316.Search in Google Scholar
Hartl, F.U. and Hayer-Hartl, M. (2002). Molecular chaperones in the cytosol: from nascent chain to folded protein. Science295, 1852–1858.10.1126/science.1068408Search in Google Scholar
Hatters, D.M., Minton, A.P., and Howlett, G.J. (2002). Macromolecular crowding accelerates amyloid formation by human apolipoprotein C-II. J. Biol. Chem.277, 7824–7830.10.1074/jbc.M110429200Search in Google Scholar
Jaenicke, R. and Seckler, R. (1997). Protein misassembly in vitro. Adv. Protein Chem.50, 1–53.10.1016/S0065-3233(08)60318-6Search in Google Scholar
Kiseleva, E.V. (1989). Secretory protein synthesis in Chironomus salivary gland cells is not coupled with protein translocation across endoplasmic reticulum membranes. FEBS Lett.257, 251–253.10.1016/0014-5793(89)81545-5Search in Google Scholar
Kocisko, D.A., Priola, S.A., Raymond, D.J., Chesbro, B., Lansbury, P.T., and Caughey, B. (1995). Species specificity in the cell-free conversion of prion protein to protease-resistant forms: a model for the scrapie species barrier. Proc. Natl. Acad. Sci. USA92, 3923–3927.10.1073/pnas.92.9.3923Search in Google Scholar
Laurent, T.C. (1963). The interaction between polysaccharides and other macromolecules. The solubility of proteins in the presence of dextran. Biochem. J.89, 253–257.Search in Google Scholar
Lazaridis, T. and Karplus, M. (1997). ‘New view’ of protein folding reconciled with the old through multiple unfolding simulations. Science278, 1928–1931.10.1126/science.278.5345.1928Search in Google Scholar
Lebowitz, J.L., Helfand, E., and Praestgaard, E. (1965). Scaled particle theory of fluid mixtures. J. Chem. Phys.43, 774–779.10.1063/1.1696842Search in Google Scholar
Li, J., Zhang, S., and Wang, C.-C. (2001) Effects of macromolecular crowding on the refolding of glucose-6-phosphate dehydrogenase and protein disulfide isomerase. J. Biol. Chem.276, 34396–34401.10.1074/jbc.M103392200Search in Google Scholar
Lindner, R.A. and Ralston, G.B. (1997). Macromolecular crowding: effects on actin polymerization. Biophys. Chem.66, 57–66.10.1016/S0301-4622(97)00011-2Search in Google Scholar
London, J., Skrzynia, C., and Goldberg, M. (1974). Renaturation of Escherichia coli tryptophanase in aqueous urea solutions. Eur. J. Biochem.47, 409–415.10.1111/j.1432-1033.1974.tb03707.xSearch in Google Scholar PubMed
Martin, J. (2002). Requirement for GroEL/GroES-dependent protein folding under non-permissive conditions of macromolecular crowding. Biochemistry41, 5050–5055.10.1021/bi015925lSearch in Google Scholar
Martin, J. (2004). Chaperonin function – effects of crowding and confinement. J. Mol. Recognit.17, 465–472.10.1002/jmr.707Search in Google Scholar
Martin, J. and Hartl, F.U. (1997). The effect of macromolecular crowding on chaperonin-mediated protein folding. Proc. Natl. Acad. Sci. USA94, 1107–1112.10.1073/pnas.94.4.1107Search in Google Scholar
Minton, A.P. (1981). Excluded volume as a determinant of macromolecular structure and reactivity. Biopolymers20, 2093–2120.10.1002/bip.1981.360201006Search in Google Scholar
Minton, A.P. (1983). The effect of volume occupancy upon the thermodynamic activity of proteins: some biochemical consequences. Mol. Cell. Biochem.55, 119–140.10.1007/BF00673707Search in Google Scholar
Minton, A.P. (1992). Confinement as a determinant of macromolecular structure. Biophys. J.63, 1090–1100.10.1016/S0006-3495(92)81663-6Search in Google Scholar
Minton, A.P. (1998). Molecular crowding: analysis of effects of high concentrations of inert cosolutes on biochemical equilibria and rates in terms of volume exclusion. Methods Enzymol.295127–149.10.1016/S0076-6879(98)95038-8Search in Google Scholar
Minton, A.P. (2000). Implications of macromolecular crowding for protein assembly. Curr. Opin. Struct. Biol.10, 34–39.10.1016/S0959-440X(99)00045-7Search in Google Scholar
Minton, A.P. (2001a). The influence of macromolecular crowding and macromolecular confinement on biochemical reactions in physiological media. J. Biol. Chem.276, 10577–10580.10.1074/jbc.R100005200Search in Google Scholar
Minton, A.P. (2001b). Effects of excluded surface area and adsorbate clustering on surface adsorption of proteins. II. Kinetic models. Biophys. J.80, 1641–1648.10.1016/S0006-3495(01)76136-XSearch in Google Scholar
Minton, K.W., Karmin, P., Hahn, G.M., and Minton, A.P. (1982). Nonspecific stabilization of stress-susceptible proteins by stress-resistant proteins: a model for the biological role of heat shock proteins. Proc. Natl. Acad. Sci. USA79, 7107–7111.10.1073/pnas.79.23.7107Search in Google Scholar
Ogston, A.G. (1958). The spaces in a uniform random suspension of fibres. Trans. Faraday Soc.5, 1754–1757.10.1039/tf9585401754Search in Google Scholar
Rivas, G., Fernandez, J.A., and Minton, A.P. (1999). Direct observation of the self-association of dilute proteins in the presence of inert macromolecules at high concentration via tracer sedimentation equilibrium: theory, experiment, and biological significance. Biochemistry38, 9379–9388.10.1021/bi990355zSearch in Google Scholar
Rivas, G., Fernandez, J.A., and Minton, A.P. (2001). Direct observation of the enhancement of non-cooperative protein self-assembly by macromolecular crowding: indefinite linear self-association of bacterial cell division protein FtsZ. Proc. Natl. Acad. Sci. USA98, 3150–3155.10.1073/pnas.051634398Search in Google Scholar
Ross, P.D. and Minton, A.P. (1977). Analysis of nonideal behavior in concentrated hemoglobin solutions. J. Mol. Biol.112, 437–452.10.1016/S0022-2836(77)80191-5Search in Google Scholar
Ross, P.D. and Minton, A.P. (1979). The effect of non-aggregating proteins upon the gelation of sickle cell hemoglobin: model calculations and data analysis. Biochem. Biophys. Res. Commun.88, 1308–1314.10.1016/0006-291X(79)91123-9Search in Google Scholar
Sasahara, K., McPhie, P., and Minton, A.P. (2004). Effect of dextran on protein stability and conformation attributed to macromolecular crowding. J. Mol. Biol.326, 1227–1237.Search in Google Scholar
Shtilerman, M.D., Ding, T.T., and Lansbury, P.T. (2002). Molecular crowding accelerates fibrillization of α-synuclein: could an increase in the cytoplasmic protein concentration induce Parkinson's disease? Biochemistry41, 3855–3860.10.1021/bi0120906Search in Google Scholar
Soti, C. and Csermely, P. (2000). Molecular chaperones and the aging process. Biogerentology1, 225–233.10.1023/A:1010082129022Search in Google Scholar
Speed, M.A., Wang, D.I.C., and King, J. (1996). Specific aggregation of partially folded polypeptide chains: the molecular basis of inclusion body composition. Nat. Biotechnol.14, 1283–1287.10.1038/nbt1096-1283Search in Google Scholar
Sunde, M. and Blake, C. (1997). The structure of amyloid fibrils by electron microscopy and X-ray diffraction. Adv. Protein Chem.50, 123–160.10.1016/S0065-3233(08)60320-4Search in Google Scholar
Takagi, F., Koga, N., and Takada, S. (2003). How protein thermodynamics and folding are altered by the chaperonin cage: molecular simulations. Proc. Natl. Acad. Sci. USA100, 11367–11372.10.1073/pnas.1831920100Search in Google Scholar
Tokuriki, N., Kinjo, M., Negi, S., Hoshino, M., Goto, Y., Urabe, I., and Yomo, T. (2004). Protein folding by the effects of macromolecular crowding. Protein Sci.13, 125–133.10.1110/ps.03288104Search in Google Scholar
Uversky, V.N., Cooper, E.M., Bower, J.I., and Fink, A.L. (2002). Accelerated α-synuclein fibrillation in crowded mileu. FEBS Lett.515, 99–103.10.1016/S0014-5793(02)02446-8Search in Google Scholar
Van den Berg, B., Ellis, R.J., and Dobson, C.M. (1999). Effects of macromolecular crowding on protein folding and aggregation. EMBO J.18, 6927–6933.10.1093/emboj/18.24.6927Search in Google Scholar
Van den Berg, B., Wain, R., Dobson, C.M., and Ellis, R.J. (2000). Macromolecular crowding perturbs protein refolding kinetics: implications for folding inside the cell. EMBO J.19, 3870–3875.10.1093/emboj/19.15.3870Search in Google Scholar
Walsh, D.M., Klyubin, I., Fadeeva, J.V., Cullen, W.K., Anwyl, R., Wolfe, M.S., Rowan, M.J., and Selkoe, D.J. (2002). Naturally secreted oligomers of amyloid-protein potently inhibit hippocampal long-term potentiation in vivo. Nature416, 535–539.10.1038/416535aSearch in Google Scholar
Wenner, J.R. and Bloomfield, V.A. (1999). Crowding effects on EcoRV kinetics and binding. Biophys. J.77, 3234–3241.10.1016/S0006-3495(99)77154-7Search in Google Scholar
Wilf, J., Gladner, J.A., and Minton, A.P. (1985). Acceleration of fibrin gel formation by unrelated proteins. Thromb. Res.37, 681–688.10.1016/0049-3848(85)90197-5Search in Google Scholar
Zettmeissl, G., Rudolph, R., and Jaenicke, R. (1979). Reconstitution of lactic dehydrogenase. Noncovalent aggregation vs. reactivation. Biochemistry18, 5567–5571.Search in Google Scholar
Zhou, H.-X. and Dill, K.A. (2001). Stabilization of proteins in confined spaces. Biochemistry40, 1289–1293.10.1021/bi0155504Search in Google Scholar PubMed
Zimmerman, S.B. and Minton, A.P. (1993). Macromolecular crowding: biochemical, biophysical, and physiological consequences. Annu. Rev. Biophys. Biomol. Struct.22, 27–65.10.1146/annurev.bb.22.060193.000331Search in Google Scholar PubMed
Zimmerman, S.B. and Trach, S.O. (1991). Estimation of macromolecule concentrations and excluded volume effects for the cytoplasm of E. coli. J. Mol. Biol.222, 599–620.10.1016/0022-2836(91)90499-VSearch in Google Scholar
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