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Protein folding and misfolding: mechanism and principles

Published online by Cambridge University Press:  14 April 2008

S. Walter Englander ,
Leland Mayne  and
Mallela M. G. Krishna
S. Walter Englander*
Affiliation:
The Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, USA
Leland Mayne
Affiliation:
The Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, USA
Mallela M. G. Krishna
Affiliation:
The Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, USA Department of Pharmaceutical Sciences and Biomolecular Structure Program, University of Colorado Health Sciences Center, Denver, CO, USA
*
*Author for correspondence: Dr S. W. Englander, Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104-6059, USA. Tel.: 215-898-4509; Fax: 215-898-2415; Email: [email protected]
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Abstract

Two fundamentally different views of how proteins fold are now being debated. Do proteins fold through multiple unpredictable routes directed only by the energetically downhill nature of the folding landscape or do they fold through specific intermediates in a defined pathway that systematically puts predetermined pieces of the target native protein into place? It has now become possible to determine the structure of protein folding intermediates, evaluate their equilibrium and kinetic parameters, and establish their pathway relationships. Results obtained for many proteins have serendipitously revealed a new dimension of protein structure. Cooperative structural units of the native protein, called foldons, unfold and refold repeatedly even under native conditions. Much evidence obtained by hydrogen exchange and other methods now indicates that cooperative foldon units and not individual amino acids account for the unit steps in protein folding pathways. The formation of foldons and their ordered pathway assembly systematically puts native-like foldon building blocks into place, guided by a sequential stabilization mechanism in which prior native-like structure templates the formation of incoming foldons with complementary structure. Thus the same propensities and interactions that specify the final native state, encoded in the amino-acid sequence of every protein, determine the pathway for getting there. Experimental observations that have been interpreted differently, in terms of multiple independent pathways, appear to be due to chance misfolding errors that cause different population fractions to block at different pathway points, populate different pathway intermediates, and fold at different rates. This paper summarizes the experimental basis for these three determining principles and their consequences. Cooperative native-like foldon units and the sequential stabilization process together generate predetermined stepwise pathways. Optional misfolding errors are responsible for 3-state and heterogeneous kinetic folding.

Type
Review Article
Information
Quarterly Reviews of Biophysics , Volume 40 , Issue 4 , November 2007 , pp. 1 - 41
Copyright
Copyright © Cambridge University Press 2008

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References

Anfinsen, C. B. (1973). Principles that govern the folding of protein chains. Science 181, 223–230.CrossRefGoogle ScholarPubMed
Anfinsen, C. B., Haber, E., Sela, M. & White, F. H. (1961). Kinetics of formation of native ribonuclease during oxidation of reduced polypeptide chain. Proceedings of the National Academy of Sciences USA 47, 1309–1314.CrossRefGoogle ScholarPubMed
Bahar, I., Wallqvist, A., Covell, D. G. & Jernigan, R. L. (1998). Correlation between native-state hydrogen exchange and cooperative residue fluctuations from a simple model. Biochemistry 37, 1067–1075.CrossRefGoogle ScholarPubMed
Bai, Y., Englander, J. J., Mayne, L., Milne, J. S. & Englander, S. W. (1995a). Thermodynamic parameters from hydrogen exchange measurements. Methods in Enzymology 259, 344–356.CrossRefGoogle ScholarPubMed
Bai, Y. & Englander, S. W. (1996). Future directions in folding: the multi-state nature of protein structure. Proteins: Structure, Function, Genetics 24, 145–151.3.0.CO;2-I>CrossRefGoogle ScholarPubMed
Bai, Y., Milne, J. S., Mayne, L. & Englander, S. W. (1993). Primary structure effects on peptide group hydrogen exchange. Proteins: Structure, Function, Genetics 17, 75–86.CrossRefGoogle ScholarPubMed
Bai, Y., Milne, J. S., Mayne, L. & Englander, S. W. (1994). Protein stability parameters measured by hydrogen exchange. Proteins: Structure, Function, Genetics 20, 4–14.CrossRefGoogle ScholarPubMed
Bai, Y., Sosnick, T. R., Mayne, L. & Englander, S. W. (1995b). Protein folding intermediates: native-state hydrogen exchange. Science 269, 192–197.CrossRefGoogle ScholarPubMed
Baum, J., Dobson, C. M., Evans, P. A. & Hanley, C. (1989). Characterization of a partly folded protein by NMR methods: studies on the molten globule state of guinea pig alpha-lactalbumin. Biochemistry 28, 7–13.CrossRefGoogle ScholarPubMed
Bédard, S., Mayne, L., Peterson, R. W., Wand, A. J. & Englander, S. W. (2008). The foldon substructure of staphylococcal nuclease. Journal of Molecular Biology 376, 1142–1154.CrossRefGoogle ScholarPubMed
Bertagna, A. M. & Barrick, D. (2004). Nonspecific hydrophobic interactions stabilize an equilibrium intermediate of apomyoglobin at a key position within the AGH region. Proceedings of the National Academy of Sciences USA 101, 12514–12519.CrossRefGoogle Scholar
Bieri, O. & Kiefhaber, T. (2001). Origin of apparent fast and non-exponential kinetics of lysozyme folding measured in pulsed hydrogen exchange measurements. Journal of Molecular Biology 310, 919–935.CrossRefGoogle Scholar
Bieri, O., Wildegger, G., Bachmann, A., Wagner, C. & Kiefhaber, T. (1999). A salt-induced kinetic intermediate is on a new parallel pathway of lysozyme folding. Biochemistry 38, 12460–12470.CrossRefGoogle ScholarPubMed
Bilsel, O., Zitzewitz, J. A., Bowers, K. E. & Matthews, C. R. (1999). Folding mechanism of the a-subunit of tryptophan synthase, an a/b barrel protein: global analysis highlights the interconversion of multiple native, intermediate, and unfolded forms through parallel channels. Biochemistry 38, 1018–1029.CrossRefGoogle Scholar
Bollen, Y. J. M., Kamphuis, M. B. & van Mierlo, C. P. M. (2006). The folding energy landscape of apoflavodoxin is rugged: hydrogen exchange reveals nonproductive misfolded intermediates. Proceedings of the National Academy of Sciences USA 103, 4095–4100.CrossRefGoogle ScholarPubMed
Bryngelson, J. D., Onuchic, J. N., Socci, N. D. & Wolynes, P. G. (1995). Funnels, pathways, and the energy landscape of protein folding: a synthesis. Proteins: Structure, Function, and Genetics 21, 167–195.CrossRefGoogle ScholarPubMed
Capaldi, A. P., Kleanthous, C. & Radford, S. E. (2002). Im7 folding mechanism: misfolding on a path to the native state. Nature Structural Biology 9, 209–216.Google Scholar
Cavagnero, S., Dyson, H. J. & Wright, P. E. (1999). Effect of H helix destabilizing mutations on the kinetic and equilibrium folding of apomyoglobin. Journal of Molecular Biology 285, 269–282.CrossRefGoogle ScholarPubMed
Cecconi, C., Shank, E. A., Bustamante, C. & Marqusee, S. (2005). Direct observation of the three-state folding of a single protein molecule. Science 309, 2057–2060.CrossRefGoogle ScholarPubMed
Cellitti, J., Bernstein, R. & Marqusee, S. (2007). Exploring subdomain cooperativity in T4 lysozyme II: uncovering the C-terminal subdomain as a hidden intermediate in the kinetic folding pathway. Protein Science 16, 852–862.CrossRefGoogle ScholarPubMed
Chamberlain, A. K., Fischer, K. F., Reardon, D., Handel, T. M. & Marqusee, A. S. (1999). Folding of an isolated ribonuclease H core fragment. Protein Science 8, 2251–2257.CrossRefGoogle ScholarPubMed
Chamberlain, A. K., Handel, T. M. & Marqusee, S. (1996). Detection of rare partially folded molecules in equilibrium with the native conformation of RNase H. Nature Structural Biology 3, 782–787.CrossRefGoogle Scholar
Chamberlain, A. K. & Marqusee, S. (2000). Comparison of equilibrium and kinetic approaches for determining protein folding mechanisms. Advances in Protein Chemistry 53, 283–328.CrossRefGoogle ScholarPubMed
Chan, H. S., Shimizu, S. & Kaya, H. (2004). Cooperativity principles in protein folding. Methods in Enzymology 380, 350–379.CrossRefGoogle ScholarPubMed
Chi, E. Y., Krishnan, S., Randolph, T. W. & Carpenter, J. F. (2003). Physical stability of proteins in aqueous solution: mechanism and driving forces in nonnative protein aggregation. Pharmaceutical Research 20, 1325–1336.CrossRefGoogle ScholarPubMed
Chu, R., Pei, W., Takei, J. & Bai, Y. (2002). Relationship between native-state hydrogen exchange and the folding pathway of a four-helix bundle protein. Biochemistry 41, 7998–8003.CrossRefGoogle ScholarPubMed
Clarke, J. & Fersht, A. R. (1996). An evaluation of the use of hydrogen exchange at equilibrium to probe intermediates on the protein folding pathway. Folding & Design 1, 243–254.CrossRefGoogle ScholarPubMed
Colon, W., Elove, G. A., Wakem, L. P., Sherman, F. & Roder, H. (1996). Side chain packing of the N- and C-terminal helices plays a critical role in the kinetics of cytochrome c folding. Biochemistry 35, 5538–5549.CrossRefGoogle Scholar
Connelly, G. P., Bai, Y., Jeng, M.-F., Mayne, L. & Englander, S. W. (1993). Isotope effects in peptide group hydrogen exchange. Proteins: Structure, Function, Genetics 17, 87–92.CrossRefGoogle ScholarPubMed
Creighton, T. E. (1986). Disulfide bonds as probes of protein folding pathways. Methods in Enzymology 131, 83–106.CrossRefGoogle ScholarPubMed
Dabora, J. M., Pelton, J. G. & Marqusee, S. (1996). Structure of the acid state of Escherichia coli ribonuclease HI. Biochemistry 35, 11951–11958.CrossRefGoogle ScholarPubMed
De Lorenzo, F., Goldberger, R., Steers, E. J., Givol, D. & Anfinsen, C. B. (1966). Purification and properties of an enzyme from beef liver which catalyzes sulfhydryl-disulfide interchange in proteins. Journal of Biological Chemistry 241, 1562–1567.CrossRefGoogle ScholarPubMed
Dill, K. A. (1985). Theory for the folding and stability of globular proteins. Biochemistry 24, 1501–1509.CrossRefGoogle ScholarPubMed
Dyson, H. J. & Wright, P. E. (2002). Coupling of folding and binding for unstructured proteins. Current Opinion in Structural Biology 12, 54–60.CrossRefGoogle ScholarPubMed
Eliezer, D., Chung, J., Dyson, H. J. & Wright, P. E. (2000). Native and non-native secondary structure and dynamics in the pH 4 intermediate of apomyoglobin. Biochemistry 39, 2894–2901.CrossRefGoogle Scholar
Elöve, G. A., Bhuyan, A. K. & Roder, H. (1994). Kinetic mechanism of cytochrome c folding: involvement of the heme and its ligands. Biochemistry 33, 6925–6935.CrossRefGoogle ScholarPubMed
Englander, J. J., Del Mar, C., Li, W., Englander, S. W., Kim, J. S., Stranz, D. D., Hamuro, Y. & Woods, V. L. J. (2003). Protein structure change studied by hydrogen-deuterium exchange, functional labeling, and mass spectrometry. Proceedings of the National Academy of Sciences USA 100, 7057–7062.CrossRefGoogle ScholarPubMed
Englander, J. J., Louie, G., McKinnie, R. E. & Englander, S. W. (1998a). Energetic components of the allosteric machinery in hemoglobin measured by hydrogen exchange. Journal of Molecular Biology 284, 1695–1706.CrossRefGoogle ScholarPubMed
Englander, J. J., Rogero, J. R. & Englander, S. W. (1985). Protein hydrogen exchange studied by the fragment separation method. Analytical Biochemistry 147, 234–244.CrossRefGoogle ScholarPubMed
Englander, S. W. (1963). A hydrogen exchange method using tritium and Sephadex. Application to ribonuclease. Biochemistry 2, 798–807.CrossRefGoogle ScholarPubMed
Englander, S. W. (2006). Hydrogen exchange and mass spectrometry: a historical perspective. Journal of the American Society for Mass Spectrometry 17, 1481–1489.CrossRefGoogle ScholarPubMed
Englander, S. W. & Kallenbach, N. R. (1983). Hydrogen exchange and structural dynamics of proteins and nucleic-acids. Quarterly Reviews of Biophysics 16, 521–655.CrossRefGoogle ScholarPubMed
Englander, S. W., Mayne, L., Bai, Y. & Sosnick, T. R. (1997). Hydrogen exchange: the modern legacy of Linderstrom-Lang. Protein Science 6, 1101–1109.CrossRefGoogle ScholarPubMed
Englander, S. W., Sosnick, T. R., Mayne, L. C., Shtilerman, M., Qi, P. X. & Bai, Y. W. (1998b). Fast and slow folding in cytochrome c. Accounts of Chemical Research 31, 737–744.CrossRefGoogle Scholar
Eyles, S. J. & Kaltashov, I. A. (2004). Methods to study protein dynamics and folding by mass spectrometry. Methods 34, 88–99.CrossRefGoogle ScholarPubMed
Feng, H., Takei, J., Lipsitz, R., Tjandra, N. & Bai, Y. (2003a). Specific non-native hydrophobic interactions in a hidden folding intermediate: implications for protein folding. Biochemistry 42, 12461–12465.CrossRefGoogle Scholar
Feng, H., Takei, J., Lipsitz, R., Tjandra, N. & Bai, Y. (2004). The high-resolution structure of a protein intermediate state: implications for protein folding. Protein Science 13, 219–220.Google Scholar
Feng, H., Zhou, Z. & Bai, Y. (2005a). A protein folding pathway with multiple folding intermediates at atomic resolution. Proceedings of the National Academy of Sciences USA 102, 5026–5031.CrossRefGoogle ScholarPubMed
Feng, H. Q., Vu, N. D. & Bai, Y. W. (2005b). Detection of a hidden folding intermediate of the third domain of PDZ. Journal of Molecular Biology 346, 345–353.CrossRefGoogle ScholarPubMed
Feng, Y., Liu, D. & Wang, J. (2003b). Native-like partially folded conformations and folding process revealed in the N-terminal large fragments of staphylococcal nuclease: a study by NMR spectroscopy. Journal of Molecular Biology 330, 821–837.CrossRefGoogle ScholarPubMed
Fersht, A. R. & Daggett, V. (2007). Folding and binding: implementing the game plan. Current Opinion in Structural Biology 17, 1–2.CrossRefGoogle Scholar
Fetrow, J. S. & Baxter, S. M. (1999). Assignment of 15N chemical shifts and 15N relaxation measurements for oxidized and reduced iso-1-cytochrome c. Biochemistry 38, 4480–4492.CrossRefGoogle ScholarPubMed
Fetrow, J. S., Dreher, U., Wiland, D. J., Schaak, D. L. & Boose, T. L. (1998). Mutagenesis of histidine 26 demonstrates the importance of loop-loop and loop-protein interactions for the function of iso-1-cytochrome c. Protein Science 7, 994–1005.CrossRefGoogle ScholarPubMed
Fine, R., Dimmler, G. & Levinthal, C. (1991). Fastrun – a special purpose, hardwired computer for molecular simulation. Proteins: Structure, Function, Genetics 11, 242–253.CrossRefGoogle ScholarPubMed
Fischer, K. F. & Marqusee, S. (2000). A rapid test for identification of autonomous folding units in proteins. Journal of Molecular Biology 302, 701–712.CrossRefGoogle ScholarPubMed
Fuentes, E. J. & Wand, A. J. (1998a). Local dynamics and stability of apocytochrome b562 examined by hydrogen exchange. Biochemistry 37, 3687–3698.CrossRefGoogle ScholarPubMed
Fuentes, E. J. & Wand, A. J. (1998b). Local stability and dynamics of apocytochrome b562 examined by the dependence of hydrogen exchange on hydrostatic pressure. Biochemistry 37, 9877–9883.CrossRefGoogle ScholarPubMed
Garcia, A. E. & Hummer, G. (1999). Conformational dynamics of cytochrome c: correlation to hydrogen exchange. Proteins: Structure, Function, Genetics 36, 175–191.3.0.CO;2-R>CrossRefGoogle ScholarPubMed
Garcia, C., Nishimura, C., Cavagnero, S., Dyson, H. J. & Wright, P. E. (2000). Changes in the apomyoglobin folding pathway caused by mutation of the distal histidine residue. Biochemistry 39, 11227–11237.CrossRefGoogle ScholarPubMed
Gualfetti, P. J., Bilsel, O. & Matthews, C. R. (1999). The progressive development of structure and stability during the equilibrium folding of the alpha subunit of tryptophan synthase from Escherichia coli. Protein Science 8, 1623–1635.CrossRefGoogle ScholarPubMed
Hernandez, G., Jenney, F. E., Adams, M. W. W. & LeMaster, D. M. (2000). Millisecond time scale conformational flexibility in a hyperthermophile protein at ambient temperature. Proceedings of the National Academy of Sciences USA 97, 3166–3170.CrossRefGoogle Scholar
Hilser, V. J., Garcia-Moreno, B. E., Oas, T. G., Kapp, G. & Whitten, S. T. (2006). A statistical thermodynamic model of the protein ensemble. Chemical Reviews 106, 1545–1558.CrossRefGoogle ScholarPubMed
Hoang, L., Bédard, S., Krishna, M. M. G., Lin, Y. & Englander, S. W. (2002). Cytochrome c folding pathway: kinetic native-state hydrogen exchange. Proceedings of the National Academy of Sciences USA 99, 12173–12178.CrossRefGoogle ScholarPubMed
Hoang, L., Maity, H., Krishna, M. M., Lin, Y. & Englander, S. W. (2003). Folding units govern the cytochrome c alkaline transition. Journal of Molecular Biology 331, 37–43.CrossRefGoogle ScholarPubMed
Hollien, J. & Marqusee, S. (1999). A thermodynamic comparison of mesophilic and thermophilic ribonucleases H. Biochemistry 38, 3831–3836.CrossRefGoogle ScholarPubMed
Hughson, F. M., Wright, P. E. & Baldwin, R. L. (1990). Structural characterization of a partly folded apomyoglobin intermediate. Science 249, 1544–1548.CrossRefGoogle ScholarPubMed
Huyghues-Despointes, B. M., Pace, C. N., Englander, S. W. & Scholtz, J. M. (2001). Measuring the conformational stability of a protein by hydrogen exchange. Methods in Molecular Biology 168, 69–92.Google ScholarPubMed
Hvidt, A. (1964). A discussion of the pH dependence of the hydrogen-deuterium exchange of proteins. Comptes Rendus des Travaux du Laboratoire Carlsberg Séries Chimique 34, 299–317.Google Scholar
Hvidt, A. & Nielsen, S. O. (1966). Hydrogen exchange in proteins. Advances in Protein Chemistry 21, 287–386.CrossRefGoogle ScholarPubMed
Jamin, M., Yeh, S. R., Rousseau, D. L. & Baldwin, R. L. (1999). Submillisecond unfolding kinetics of apomyoglobin and its pH 4 intermediate. Journal of Molecular Biology 292, 731–740.CrossRefGoogle Scholar
Jemmerson, R., Liu, J., Hausauer, D., Lam, K.-P., Mondino, A. & Nelson, R. D. (1999). A conformational change in cytochrome c of apoptotic and necrotic cells is detected by monoclonal antibody binding and mimicked by association of the native antigen with synthetic phospholipid vesicles. Biochemistry 38, 3599–3609.CrossRefGoogle ScholarPubMed
Jeng, M. F., Englander, S. W., Elöve, G. A., Wand, A. J. & Roder, H. (1990). Structural description of acid-denatured cytochrome c by hydrogen exchange and 2D NMR. Biochemistry 29, 10433–10437.CrossRefGoogle Scholar
Jennings, P. A. & Wright, P. E. (1993). Formation of a molten globule intermediate early in the kinetic folding pathway of apomyoglobin. Science 262, 892–896.CrossRefGoogle ScholarPubMed
Kamagata, K., Sawano, Y., Tanokura, M. & Kuwajima, K. (2003). Multiple parallel-pathway folding of proline-free staphylococcal nuclease. Journal of Molecular Biology 332, 1143–1153.CrossRefGoogle ScholarPubMed
Kato, H., Vu, N. D., Feng, H. Q., Zhou, Z. & Bai, Y. W. (2007). The folding pathway of T4 lysozyme: an on-pathway hidden folding intermediate. Journal of Molecular Biology 365, 881–891.CrossRefGoogle ScholarPubMed
Kelly, J. W., Colon, W., Lai, Z., Lashuel, H. A., McCulloch, J., McCutchen, S. L., Miroy, G. J. & Peterson, S. A. (1997). Transthyretin quaternary and tertiary structural changes facilitate misassembly into amyloid. Advances in Protein Chemistry 50, 161–181.CrossRefGoogle ScholarPubMed
Kiefhaber, T. (1995). Kinetic traps in lysozyme folding. Proceedings of the National Academy of Sciences USA 92, 9029–9033.CrossRefGoogle ScholarPubMed
Kiefhaber, T., Bachmann, A., Wildegger, G. & Wagner, C. (1997). Direct measurement of nucleation and growth rates in lysozyme folding. Biochemistry 36, 5108–5112.CrossRefGoogle ScholarPubMed
Kihara, H., Saigo, S., Nakatani, H., Hiromi, K., Ikeda-Saito, M. & Iizuka, T. (1976). Kinetic study of isomerization of ferricytochrome c at alkaline pH. Biochimica et Biophysica Acta 430, 225–243.CrossRefGoogle ScholarPubMed
Kim, K. S., Fuchs, J. A. & Woodward, C. K. (1993). Hydrogen exchange identifies native-state motional domains important in protein folding. Biochemistry 32, 9600–9608.CrossRefGoogle ScholarPubMed
Kim, P. S. & Baldwin, R. L. (1982a). Influence of charge on the rate of amide proton exchange. Biochemistry 21, 1–5.CrossRefGoogle ScholarPubMed
Kim, P. S. & Baldwin, R. L. (1982b). Specific intermediates in the folding reactions of small proteins and the mechanism of protein folding. Annual Review of Biochemistry 51, 459–489.CrossRefGoogle ScholarPubMed
Kim, P. S. & Baldwin, R. L. (1990). Intermediates in the folding reactions of small proteins. Annual Review of Biochemistry 59, 631–660.CrossRefGoogle ScholarPubMed
Korzhnev, D. M., Neudecker, P., Zarrine-Afsar, A., Davidson, A. R. & Kay, L. E. (2006). Abp1p and Fyn SH3 domains fold through similar low-populated intermediate states. Biochemistry 45, 10175–10183.CrossRefGoogle ScholarPubMed
Korzhnev, D. M., Religa, T. L., Lundstrom, P., Fersht, A. R. & Kay, L. E. (2007). The folding pathway of an FF domain: characterization of an on-pathway intermediate state under folding conditions by (15)N, (13)C(alpha) and (13)C-methyl relaxation dispersion and (1)H/(2)H-exchange NMR spectroscopy. Journal of Molecular Biology 372, 497–512.CrossRefGoogle Scholar
Korzhnev, D. M., Salvatella, X., Vendruscolo, M., Nardo, A. A. D., Davidson, A. R., Dobson, C. M. & Kay, L. E. (2004). Low-populated folding intermediates of Fyn SH3 characterized by relaxation dispersion NMR. Nature 430, 586–590.CrossRefGoogle ScholarPubMed
Krantz, B. A., Dothager, R. S. & Sosnick, T. R. (2004). Discerning the structure and energy of multiple transition states in protein folding using y-analysis. Journal of Molecular Biology 337, 463–475.CrossRefGoogle Scholar
Krishna, M. M. G. & Englander, S. W. (2005). The N-terminal to C-terminal motif in protein folding and function. Proceedings of the National Academy of Sciences USA 102, 1053–1058.CrossRefGoogle ScholarPubMed
Krishna, M. M. G. & Englander, S. W. (2007). A unified mechanism for protein folding: predetermined pathways with optional errors. Protein Science 16, 449–464.CrossRefGoogle ScholarPubMed
Krishna, M. M. G., Hoang, L., Lin, Y. & Englander, S. W. (2004a). Hydrogen exchange methods to study protein folding. Methods 34, 51–64.CrossRefGoogle ScholarPubMed
Krishna, M. M. G., Lin, Y. & Englander, S. W. (2004b). Protein misfolding: optional barriers, misfolded intermediates, and pathway heterogeneity. Journal of Molecular Biology 343, 1095–1109.CrossRefGoogle ScholarPubMed
Krishna, M. M. G., Lin, Y., Mayne, L. & Walter Englander, S. (2003a). Intimate view of a kinetic protein folding intermediate: residue-resolved structure, interactions, stability, folding and unfolding rates, homogeneity. Journal of Molecular Biology 334, 501–513.CrossRefGoogle ScholarPubMed
Krishna, M. M. G., Lin, Y., Rumbley, J. N. & Englander, S. W. (2003b). Cooperative omega loops in cytochrome c: role in folding and function. Journal of Molecular Biology 331, 29–36.CrossRefGoogle ScholarPubMed
Krishna, M. M. G., Maity, H., Rumbley, J. N. & Englander, S. W. (2007). Branching in the sequential folding pathway of cytochrome c. Protein Science 16, 1946–1956.CrossRefGoogle ScholarPubMed
Krishna, M. M. G., Maity, H., Rumbley, J. N., Lin, Y. & Englander, S. W. (2006). Order of steps in the cytochrome c folding pathway: evidence for a sequential stabilization mechanism. Journal of Molecular Biology 359, 1411–1420.CrossRefGoogle ScholarPubMed
Leopold, P. E., Montal, M. & Onuchic, J. N. (1992). Protein folding funnels: a kinetic approach to the sequence-structure relationship. Proceedings of the National Academy of Sciences USA 89, 8721–8725.CrossRefGoogle Scholar
Leszczynski, J. F. & Rose, G. D. (1986). Loops in globular proteins: a novel category of secondary structure. Science 234, 849–855.CrossRefGoogle ScholarPubMed
Levinthal, C. (1969). How to fold graciously. In Mossbauer Spectroscopy in Biological Systems. Proceedings, University of Illinois Bulletin, vol. 67, pp. 22–24. Urbana, IL: University of Illinois Press.Google Scholar
Lifson, S. & Roig, A. (1961). On the theory of the helix-coil transition in polypeptides. Journal of Chemical Physics 34, 1963–1974.CrossRefGoogle Scholar
Linderstrøm-Lang, K. (1958). Deuterium exchange and protein structure. In Symposium on Protein Structure (edNeuberger, A.). London: Methuen.Google Scholar
Linderstrøm-Lang, K. U. & Schellman, J. A. (1959). Protein structure and enzyme activity. In The Enzymes (edsBoyer, P. D., Lardy, H. and Myrback, K.), pp. 443–510. New York: Academic Press.Google Scholar
Loh, S. N., Kay, M. S. & Baldwin, R. L. (1995). Structure and stability of a second molten globule intermediate in the apomyoglobin folding pathway. Proceedings of the National Academy of Sciences USA 92, 5446–5450.CrossRefGoogle ScholarPubMed
Loh, S. N., Prehoda, K. E., Wang, J. & Markley, J. L. (1993). Hydrogen exchange in unligated and ligated staphylococcal nuclease. Biochemistry 32, 11022–11028.CrossRefGoogle ScholarPubMed
Maity, H., Lim, W. K., Rumbley, J. N. & Englander, S. W. (2003). Protein hydrogen exchange mechanism: local fluctuations. Protein Science 12, 153–160.CrossRefGoogle ScholarPubMed
Maity, H., Maity, M. & Englander, S. W. (2004). How cytochrome c folds, and why: submolecular foldon units and their stepwise sequential stabilization. Journal of Molecular Biology 343, 223–233.CrossRefGoogle ScholarPubMed
Maity, H., Maity, M., Krishna, M. M. G., Mayne, L. & Englander, S. W. (2005). Protein folding: the stepwise assembly of foldon units. Proceedings of the National Academy of Sciences USA 102, 4741–4746.CrossRefGoogle ScholarPubMed
Maity, H., Rumbley, J. N. & Englander, S. W. (2006). Functional role of a protein foldon: an W-loop foldon controls the alkaline transition in ferricytochrome c. Proteins: Structure, Function, Genetics 63, 349–355.CrossRefGoogle Scholar
Mayne, L. & Englander, S. W. (2000). Two-state vs. multistate protein unfolding studied by optical melting and hydrogen exchange. Protein Science 9, 1873–1877.CrossRefGoogle ScholarPubMed
Milne, J. S., Mayne, L., Roder, H., Wand, A. J. & Englander, S. W. (1998). Determinants of protein hydrogen exchange studied in equine cytochrome c. Protein Science 7, 739–745.CrossRefGoogle ScholarPubMed
Milne, J. S., Xu, Y., Mayne, L. C. & Englander, S. W. (1999). Experimental study of the protein folding landscape: unfolding reactions in cytochrome c. Journal of Molecular Biology 290, 811–822.CrossRefGoogle ScholarPubMed
Molday, R. S., Englander, S. W. & Kallen, R. G. (1972). Primary structure effects on peptide group hydrogen exchange. Biochemistry 11, 150–158.CrossRefGoogle ScholarPubMed
Moult, J., Fidelis, K., Kryshtafovych, A., Rost, B., Hubbard, T. & Tramontano, A. (2007). Critical assessment of methods of protein structure prediction – round VII. Proteins: Structure Function and Bioinformatics 69, 3–9.CrossRefGoogle ScholarPubMed
Myers, J. K., Pace, C. N. & Scholtz, J. M. (1995). Denaturant m values and heat capacity changes: relation to changes in accessible surface areas of protein unfolding. Protein Science 4, 2138–2148.CrossRefGoogle ScholarPubMed
Neudecker, P., Zarrine-Afsar, A., Davidson, A. R. & Kay, L. E. (2007). Phi-value analysis of a three-state protein folding pathway by NMR relaxation dispersion spectroscopy. Proceedings of the National Academy of Sciences USA 104, 15717–15722.CrossRefGoogle ScholarPubMed
Nishimura, C., Dyson, H. J. & Wright, P. E. (2006). Identification of native and non-native structure in kinetic folding intermediates of apomyoglobin. Journal of Molecular Biology 355, 139–156.CrossRefGoogle ScholarPubMed
Oas, T. G. & Kim, P. S. (1988). A peptide model of a protein folding intermediate. Nature 336, 42–48.CrossRefGoogle ScholarPubMed
Ozkan, S. B., Wu, G. A., Chodera, J. D. & Dill, K. A. (2007). Protein folding by zipping and assembly. Proceedings of the National Academy of Sciences USA 104, 11987–11992.CrossRefGoogle ScholarPubMed
Pace, C. N. (1975). The stability of globular proteins. CRC Critical Reviews in Biochemistry 3, 1–43.CrossRefGoogle ScholarPubMed
Panchenko, A. R., Luthey schulten, Z. & Wolynes, P. G. (1996). Foldons, protein structural modules, and exons. Proceedings of the National Academy of Sciences USA 93, 2008–2013.CrossRefGoogle ScholarPubMed
Pettigrew, G. W. & Moore, G. R. (1987). Cytochromes c. Biological Aspects. Berlin Heidelberg, Germany: Springer-Verlag.CrossRefGoogle Scholar
Plaxo, K. W., Simons, K. T. & Baker, D. (1998). Contact order, transition state placement and the refolding rates of single domain proteins. Journal of Molecular Biology 277, 985–994.CrossRefGoogle Scholar
Pletneva, E. V., Gray, H. B. & Winkler, J. R. (2005). Snapshots of cytochrome c folding. Proceedings of the National Academy of Sciences USA 102, 18397–18402.CrossRefGoogle ScholarPubMed
Plotkin, S. S. & Onuchic, J. N. (2002a). Understanding protein folding with energy landscape theory. Part I: Basic concepts. Quarterly Reviews of Biophysics 35, 111–167.CrossRefGoogle ScholarPubMed
Plotkin, S. S. & Onuchic, J. N. (2002b). Understanding protein folding with energy landscape theory. Part II: Quantitative concepts. Quarterly Reviews of Biophysics 35, 205–286.CrossRefGoogle Scholar
Ptitsyn, O. B. (1995). Molten globule and protein folding. Advances in Protein Chemistry 47, 83–229.CrossRefGoogle ScholarPubMed
Radford, S. E., Dobson, C. M. & Evans, P. A. (1992). The folding of hen lysozyme involves partially structured intermediates and multiple pathways. Nature 358, 302–307.CrossRefGoogle ScholarPubMed
Raschke, T. M., Kho, J. & Marqusee, S. (1999). Confirmation of the hierarchical folding of RNase H: a protein engineering study. Nature Structural Biology 6, 825–831.Google ScholarPubMed
Raschke, T. M. & Marqusee, S. (1997). The kinetic folding intermediate of ribonuclease H resembles the acid molten globule and partially unfolded molecules detected under native conditions. Nature Structural Biology 4, 298–304.CrossRefGoogle ScholarPubMed
Roder, H., Elove, G. A. & Englander, S. W. (1988). Structural characterization of folding intermediates in cytochrome c by H-exchange labelling and proton NMR. Nature 335, 700–704.CrossRefGoogle ScholarPubMed
Rosenberg, A. & Chakravarti, K. (1968). Studies of hydrogen exchange in proteins. I. The exchange kinetics of bovine carbonic anhydrase. Journal of Biological Chemistry 243, 5193–5201.CrossRefGoogle ScholarPubMed
Rumbley, J., Hoang, L., Mayne, L. C. & Englander, S. W. (2001). An amino acid code for protein folding. Proceedings of the National Academy of Sciences USA 105, 105–112.CrossRefGoogle Scholar
Schlunegger, M. P., Bennett, M. J. & Eisenberg, D. (1997). Oligomer formation by 3D domain swapping: a model for protein assembly and misassembly. Advances in Protein Chemistry 50, 61–122.CrossRefGoogle Scholar
Schmid, F. X. & Baldwin, R. L. (1979). Detection of an early intermediate in the folding of ribonuclease A by protection of amide protons against exchange. Journal of Molecular Biology 135, 199–215.CrossRefGoogle ScholarPubMed
Silverman, J. A. & Harbury, P. B. (2002a). The equilibrium unfolding pathway of a (b/a)8 barrel. Journal of Molecular Biology 324, 1031–1040.CrossRefGoogle Scholar
Silverman, J. A. & Harbury, P. B. (2002b). Rapid mapping of protein structure, interactions, and ligand binding by misincorporation proton-alkyl exchange. Journal of Biological Chemistry 277, 30968–30975.CrossRefGoogle ScholarPubMed
Sosnick, T. R., Krantz, B. A., Dothager, R. S. & Baxa, M. (2006). Characterizing the protein folding transition state using psi analysis. Chemical Reviews 106, 1862–1876.CrossRefGoogle ScholarPubMed
Sosnick, T. R., Mayne, L. & Englander, S. W. (1996). Molecular collapse: the rate-limiting step in two-state cytochrome c folding. Proteins: Structure, Function, Genetics 24, 413–426.3.0.CO;2-F>CrossRefGoogle ScholarPubMed
Sosnick, T. R., Mayne, L., Hiller, R. & Englander, S. W. (1994). The barriers in protein folding. Nature Structural Biology 1, 149–156.CrossRefGoogle ScholarPubMed
Spolaore, B., Bermejo, R., Zambonin, M. & Fontana, A. (2001). Protein interactions leading to conformational changes monitored by limited proteolysis: Apo form and fragments of horse cytochrome c. Biochemistry 40, 9460–9468.CrossRefGoogle ScholarPubMed
Sugase, K., Dyson, H. J. & Wright, P. E. (2007). Mechanism of coupled folding and binding of an intrinsically disordered protein. Nature 447, 1021–1025.CrossRefGoogle ScholarPubMed
Takei, J., Pei, W., Vu, D. & Bai, Y. (2002). Populating partially unfolded forms by hydrogen exchange-directed protein engineering. Biochemistry 41, 12308–12312.CrossRefGoogle ScholarPubMed
Udgaonkar, J. B. & Baldwin, R. L. (1988). NMR evidence for an early framework intermediate on the folding pathway of ribonuclease A. Nature 335, 694–699.CrossRefGoogle ScholarPubMed
Vendrusculo, M., Paci, E., Dobson, C. M. & Karplus, M. (2003). Rare fluctuations of native proteins sampled by equilibrium hydrogen exchange. Journal of the American Chemical Society 125, 15686–15687.CrossRefGoogle Scholar
Vu, N. T., Feng, H. & Bai, Y. (2004). The folding pathway of barnase: the rate-limiting transition state and a hidden intermediate under native conditions. Protein Science 13, 220–220.Google Scholar
Wagner, G. & Wüthrich, K. (1982). Amide proton exchange and surface conformation of BPTI in solution: studies with 2D NMR. Journal of Molecular Biology 160, 343–361.CrossRefGoogle Scholar
Wallace, L. A. & Matthews, C. R. (2002). Sequential vs. parallel protein-folding mechanisms: experimental tests for complex folding reactions. Biophysical Chemistry 101, 113–131.CrossRefGoogle ScholarPubMed
Wand, A. J. & Englander, S. W. (1996). Protein complexes studied by NMR spectroscopy. Current Opinion in Biotechnology 7, 403–408.CrossRefGoogle ScholarPubMed
Wang, L. & Kallenbach, N. R. (1998). Proteolysis as a measure of the free energy difference between cytochrome c and its derivatives. Protein Science 7, 2460–2464.CrossRefGoogle ScholarPubMed
Watson, J. D. & Crick, F. H. C. (1953). Molecular structure of nucleic acids. A structure for deoxyribose nucleic acid. Nature 171, 737–738.CrossRefGoogle ScholarPubMed
Weinkam, P., Zong, C. & Wolynes, P. G. (2005). A fu-nneled energy landscape for cytochrome c directly predicts the sequential folding route inferred from hydrogen exchange experiments. Proceedings of the National Academy of Sciences USA 102, 12401–12406.CrossRefGoogle ScholarPubMed
Wildegger, G. & Kiefhaber, T. (1997). Three-state model for lysozyme folding: triangular folding mechanism with an energetically trapped intermediate. Journal of Molecular Biology 270, 294–304.CrossRefGoogle ScholarPubMed
Wolynes, P. G., Onuchic, J. N. & Thirumalai, D. (1995). Navigating the folding routes. Science 267, 1619–1620.CrossRefGoogle ScholarPubMed
Woodward, C. K. (1994). Hydrogen exchange rates and protein folding. Current Opinion in Structural Biology 4, 112–116.CrossRefGoogle Scholar
Woodward, C. K. & Hilton, B. D. (1979). Hydrogen exchange kinetics and internal motions in proteins and nucleic acids. Annual Review of Biophysics & Bioengineering 8, 99–127.CrossRefGoogle ScholarPubMed
Woodward, C. K., Hilton, B. D. & Tuchsen, E. (1982). Hydrogen exchange and the dynamic structure of proteins. Molecular and Cellular Biochemistry 48, 135–160.CrossRefGoogle ScholarPubMed
Wu, Y. & Matthews, C. R. (2002). Parallel channels and rate-limiting steps in complex protein folding reactions: prolyl isomerization and the alpha subunit of Trp synthase, a TIM barrel protein. Journal of Molecular Biology 323, 309–325.CrossRefGoogle ScholarPubMed
Wu, Y. & Matthews, C. R. (2003). Proline replacements and the simplification of the complex, parallel channel folding mechanism for the alpha subunit of Trp synthase, a TIM barrel protein. Journal of Molecular Biology 330, 1131–1144.CrossRefGoogle ScholarPubMed
Xu, Y., Mayne, L. & Englander, S. W. (1998). Evidence for an unfolding and refolding pathway in cytochrome c. Nature Structural Biology 5, 774–778.CrossRefGoogle ScholarPubMed
Yan, S., Gawlak, G., Smith, J., Silver, L., Koide, A. & Koide, S. (2004). Conformational heterogeneity of an equilibrium folding intermediate quantified and mapped by scanning mutagenesis. Journal of Molecular Biology 338, 811–825.CrossRefGoogle ScholarPubMed
Yan, S., Kennedy, S. D. & Koide, S. (2002). Thermodynamic and kinetic exploration of the energy landscape of Borrelia budgdorferi OspA by native-state hydrogen exchange. Journal of Molecular Biology 323, 363–375.CrossRefGoogle ScholarPubMed
Yewdell, J. W. (2005). Serendipity strikes twice: the discovery and rediscovery of defective ribosomal products (DRiPS). Cell and Molecular Biology 51, 635–641.Google ScholarPubMed
Zhang, Z. & Smith, D. L. (1993). Determination of amide hydrogen exchange by mass spectrometry: a new tool for protein structure elucidation. Protein Science 2, 522–531.CrossRefGoogle ScholarPubMed
Zhou, Z., Feng, H. & Bai, Y. (2006). Detection of a hidden folding intermediate in the focal adhesion target domain: implications for its function and folding. Proteins: Structure, Function, Genetics 65, 259–265.CrossRefGoogle ScholarPubMed
Zimm, G. H. & Bragg, J. K. (1959). Theory of the phase transition between helix and random coil in polypeptide chains. Journal of Chemical Physics 31, 526–535.CrossRefGoogle Scholar
Zwanzig, R., Szabo, A. & Bagchi, B. (1992). Levinthal's paradox. Proceedings of the National Academy of Sciences USA 89, 20–22.CrossRefGoogle ScholarPubMed