Skip to main content
SpringerLink
Log in

The Folding Pathway of Apomyoglobin

  • Chapter
Statistical Mechanics, Protein Structure, and Protein Substrate Interactions

Part of the book series: NATO ASI Series ((NSSB,volume 325))

Abstract

The detailed molecular mechanism of protein folding is currently a subject of intense interest. It is generally accepted that folding proceeds via the formation of intermediate species rather than through a random conformational search (1) However, the highly cooperative nature of the folding transition for most small proteins precludes structural characterization of intermediate species under equilibrium conditions. Spectroscopic studies of peptide fragments of proteins at equilibrium have been used to help identify regions of a protein with a high propensity to form structure in solution, and thus possible folding initiation sites (2). Kinetic studies of folding reactions have demonstrated the appearance of transient intermediates, but the lifetimes of these species are usually not compatible with detailed structural studies. Nonetheless, stopped-flow studies have provided valuable insights into the formation of folding intermediates. The development of pulsed amide proton exchange experiments in combination with two-dimensional (2D) NMR methods has facilitated the acquisition of detailed structural information on transiently populated folding intermediates (3–10) and has provided considerable impetus to the elucidation of protein folding pathways and the generalized mechanism of protein folding.

To whom correspondence should be addressed

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. P.S. Kim and R.L. Baldwin, Specific intermediates in the folding reactions of small proteins and the mechanism of protein folding. Ann. Rev. Biochem., 51, 459–489 (1982).

    Article  PubMed  CAS  Google Scholar 

  2. H.J. Dyson and P.E. Wright, Peptide conformation and protein folding. Curr. Opin. Struct. Biol., 3, 60–65 (1993).

    Article  CAS  Google Scholar 

  3. J.B. Udgaonkar and R.L. Baldwin, NMR evidence for an early framework intermediate on the folding pathway of ribonuclease A. Nature, 335, 694–699 (1988).

    Article  PubMed  CAS  Google Scholar 

  4. H. Roder, G.A. Elöve and S.W. Englander, Structural characterization of folding intermediates in cytochrome C by H-exchange labelling and proton NMR. Nature, 335, 700–704 (1988).

    Article  PubMed  CAS  Google Scholar 

  5. J.B. Udgaonkar and R.L. Baldwin, Early folding intermediate of ribonuclease A. Proc. Natl. Acad. Sci. USA, 87, 8197–8201 (1990).

    Article  PubMed  CAS  Google Scholar 

  6. M. Bycroft, A. Matouschek, J.T. Kellis Jr., L. Serrano and A.R. Fersht, Detection and characterization of a folding intermediate in barnase by NMR. Nature, 346, 488–490 (1990).

    Article  PubMed  CAS  Google Scholar 

  7. A. Matouschek, J. Kellis J. T., L. Serrano, M. Bycroft and A.R. Fersht, Transient folding intermediates characterized by protein engineering. Nature, 346, 440–445 (1990).

    Article  PubMed  CAS  Google Scholar 

  8. M.S. Briggs and H. Roder, Early hydrogen-bonding events in the folding reaction of ubiquitin. Proc. Natl. Acad. Sci. USA, 89, 2017–2021 (1992).

    Article  PubMed  CAS  Google Scholar 

  9. S.E. Radford, C.M. Dobson and P.A. Evans, The folding of hen lysozyme involves partially structured intermediates and multiple pathways. Nature, 358, 302–307 (1992).

    Article  PubMed  CAS  Google Scholar 

  10. J. Lu and F.W. Dahlquist, Detection and characterization of an early folding intermediate of T4 lysozyme using pulse hydrogen exchange and two-dimensional NMR. Biochemistry, 31, 4749–4756 (1992).

    Article  PubMed  CAS  Google Scholar 

  11. O.B. Ptitsyn and A.A. Rashin, A model of myoglobin self-organization. Biophys. Chem., 3, 1 (1975).

    Article  PubMed  CAS  Google Scholar 

  12. T.J. Richmond and F.M. Richards, Packing of α-helices: geometrical constraints and contact areas. J. Mol. Biol., 119, 537–555 (1978).

    Article  PubMed  CAS  Google Scholar 

  13. F.E. Cohen, T.J. Richmond and F.M. Richards, Protein folding: evaluation of some simple rules for the assembly of helices into tertiary structure with myoglobin as an example. J. Mol. Biol., 132, 275–288 (1979).

    Article  PubMed  CAS  Google Scholar 

  14. F.E. Cohen, M.J.E. Steinberg, D.C. Phillips, I.D. Kuntz and P.A. KoUman, A diffusion-collision-adhesion model for the kinetics of myoglobin refolding. Nature, 286, 632–634 (1980).

    Article  PubMed  CAS  Google Scholar 

  15. M. Gerritsen, K.-C. Chou, G. Nemethy and H.A. Scheraga, Energetics of multihelix interactions in protein folding: application to myoglobin. Biopolymers, 24, 1271–1291 (1985).

    Article  PubMed  CAS  Google Scholar 

  16. D. Bashford, F.E. Cohen, M. Karplus, I.D. Kuntz and D.L. Weaver, Diffusion-collision model for the folding kinetics of myoglobin. Proteins, 4, 211–227 (1988).

    Article  PubMed  CAS  Google Scholar 

  17. G. Chelvanayagam, Z. Reich, R. Bringas and P. Argos, Prediction of protein folding pathways. J. Mol. Biol., 227, 901–916 (1992).

    Article  PubMed  CAS  Google Scholar 

  18. S.R. Anderson, M. Brunori and G. Weber, Fluorescence studies of Aplysia and sperm whale apomyoglobins. Biochemistry, 9, 4723–4729 (1970).

    Article  PubMed  CAS  Google Scholar 

  19. Y.V. Griko, P.L. Privalov, S.Y. Venyaminov and V.P. Kutyshenko, Thermodynamic study of the apomyoglobin structure. J. Mol. Biol., 202, 127–138 (1988).

    Article  PubMed  CAS  Google Scholar 

  20. F.M. Hughson, P.E. Wright and R.L. Baldwin, Structural characterization of a partly folded apomyoglobin intermediate. Science, 249, 1544–1548 (1990).

    Article  PubMed  CAS  Google Scholar 

  21. P.A. Jennings and P.E. Wright, Formation of a molten globule intermediate early in the kinetic folding pathway of apomyoglobin. Science, 262, 892–896 (1993).

    Article  PubMed  CAS  Google Scholar 

  22. C.L. Brooks, Characterization of “native” apomyoglobin by molecular dynamics simulation. J. Mol. Biol., 227, 375–380 (1992).

    Article  PubMed  CAS  Google Scholar 

  23. M.J. Cocco and J.T.J. Lecomte, Characterization of hydrophobic cores in apomyoglobin: a proton NMR spectroscopy study. Biochemistry, 29, 11067–11072 (1990).

    Article  PubMed  CAS  Google Scholar 

  24. M.J. Cocco, Y.-H. Kao, A.T. Phillips and J.T.J. Lecomte, Structural comparison of apomyoglobin and metaquomyoglobin: pH titration of histidines by NMR spectroscopy. Biochemistry, 31, 6481–6491 (1992).

    Article  PubMed  CAS  Google Scholar 

  25. F.M. Hughson and R.L. Baldwin, Use of site-directed mutagenesis to destabilize native apomyoglobin relative to folding intermediates. Biochemistry, 28, 4415–4422 (1989).

    Article  PubMed  CAS  Google Scholar 

  26. F.M. Hughson, D. Barrick and R.L. Baldwin, Probing the stability of a partly folded apomyoglobin intermediate by site-directed mutagenesis. Biochemistry, 30, 4113–4118 (1991).

    Article  PubMed  CAS  Google Scholar 

  27. K. Kuwajima, The molten globule state as a clue for understanding the folding and cooperativity of globular-protein structure. Proteins, 6, 87–103 (1989).

    Article  PubMed  CAS  Google Scholar 

  28. R.L. Baldwin, Molten globules:specific or nonspecific intermediates?. Chemtracts, 2, 379–389 (1991).

    CAS  Google Scholar 

  29. O.B. Ptitsyn, Stage mechanism of self organization of protein molecules. Dokl. Akad. Nauk. SSSR, 210, 1213–1215 (1973).

    PubMed  CAS  Google Scholar 

  30. H. Christensen and R.H. Pain, Molten globule intermediates and protein folding. Eur. Biophys. J., 19, 221–229 (1991).

    Article  PubMed  CAS  Google Scholar 

  31. M.-F. Jeng, S.W. Englander, G.A. Elöve, A.J. Wand and H. Roder, Structural description of aciddenatured cytochrome c by hydrogen exchange and 2D NMR. Biochemistry, 29, 10433–10437 (1990).

    Article  PubMed  CAS  Google Scholar 

  32. M.-F. Jeng and S.W. Englander, Stable submolecular folding units in a non-compact form of cytochrome c. J. Mol. Biol., 221, 1045–1061 (1991).

    Article  PubMed  CAS  Google Scholar 

  33. J. Baum, C.M. Dobson, P.A. Evans and C. Hanley, Characterization of a partly folded protein by NMR methods: Studies on the molten globule state of guinea pig α-lactalbumin. Biochemistry, 28, 7–13 (1989).

    Article  PubMed  CAS  Google Scholar 

  34. O.B. Ptitsyn, How does protein synthesis give rise to the 3-D structure? FEBS Lett., 285, 176–181 (1991).

    Article  PubMed  CAS  Google Scholar 

  35. O.B. Ptitsyn, R.H. Pain, G.V. Semisotnov, E. Zerovnik and O.I. Razgulyaev, Evidence for a molten globule state as a general intermediate in protein folding. FEBS Lett., 262, 20–24 (1990).

    Article  PubMed  CAS  Google Scholar 

  36. R.L. Baldwin. Experimental studies of pathways of protein folding, in Protein Conformation, Ciba Foundation Symposium. 1991. Chichester: Wiley, pp 190–205.

    Google Scholar 

  37. Y. Goto, L.J. Calciano and A.L. Fink, Acid-induced folding of proteins. Proc. Natl. Acad. Sci. USA, 87, 573–577 (1990).

    Article  PubMed  CAS  Google Scholar 

  38. G. Irace, E. Bismuto, F. Savy and G. Colona, Unfolding pathway of myoglobin: molecular properties of intermediate forms. Arch. Biochem. Biophys., 244, 459–469 (1986).

    Article  PubMed  CAS  Google Scholar 

  39. D. Barrick and R.L. Baldwin, Three-state analysis of sperm whale apomyoglobin folding. Biochemistry, 32, 3790–3796 (1993).

    Article  PubMed  CAS  Google Scholar 

  40. E. Bismuto, I. Sirangelo and G. Irace, Salt-induced refolding off myoglobin at acidic pH: molecular properties of a partly folded intermediate. Arch. Biochem. Biophys., 298, 624–629 (1992).

    Article  PubMed  CAS  Google Scholar 

  41. K. Kuwajima, Y. Hiraoka, M. Ikeguchi and S. Sugai, Comparison of the transient folding intermediates in lysozyme and α-lactalbumin. Biochemistry, 24, 874–881 (1985).

    Article  PubMed  CAS  Google Scholar 

  42. G.A. Elöve and H. Roder, Structure and stability of cytochrome c folding intermediates, in “Protein Refolding”, G. Georgiou and E. De Bernardez-Clark, ed., American Chemical Society, Washington D.C. (1991) pp. 50–62.

    Chapter  Google Scholar 

  43. S.W. Englander and L. Mayne, Protein folding studied using hydrogen-exchange labeling and two-dimensional NMR. Annu. Rev. Biophys. Biomol. Struct., 21, 243–265 (1992).

    Article  PubMed  CAS  Google Scholar 

  44. P.E. Wright, H.J. Dyson and R.A. Lerner, Conformation of peptide fragments of proteins in aqueous solution: Implications for initiation of protein folding. Biochemistry, 27, 7167–7175 (1988).

    Article  PubMed  CAS  Google Scholar 

  45. H.J. Dyson and P.E. Wright, Defining solution conformations of small linear peptides. Annu. Rev. Biophys. Biophys. Chem., 20, 519–538 (1991).

    Article  PubMed  CAS  Google Scholar 

  46. H.J. Dyson, G. Merutka, J.P. Waltho, R.A. Lerner and P.E. Wright, Folding of peptide fragments comprising the complete sequence of proteins: Models for initation of protein folding. I. Myohemerythrin. J. Mol. Biol., 226, 795–817 (1992).

    Article  PubMed  CAS  Google Scholar 

  47. H.J. Dyson, J.R. Sayre, G. Merutka, H.-C. Shin, R.A. Lerner and P.E. Wright, Folding of peptide fragments comprising the complete sequence of proteins: Models for initiation of protein folding. II. Plastocyanin. J. Mol. Biol., 226, 819–835 (1992).

    Article  PubMed  CAS  Google Scholar 

  48. R.R. Matheson and H.A. Scheraga, A method for predicting nucleation sites for protein folding based on hydrophobic contacts. Macromolecules, 11, 819–829 (1978).

    Article  CAS  Google Scholar 

  49. J.P. Waltho, V.A. Feher, R.A. Lerner and P.E. Wright, Conformation of a T-cell stimulating peptide in aqueous solution. FEBS Lett., 250, 400–404 (1989).

    Article  PubMed  CAS  Google Scholar 

  50. J.P. Waltho, V.A. Feher and P.E. Wright, The H-helix of myoglobin as a potential independent protein folding domain. Curr. Res. Prot. Chem., 283-293 (1990).

    Google Scholar 

  51. J.P. Waltho, V.A. Feher, G. Merutka, H.J. Dyson and P.E. Wright, Peptide models of protein folding initiation sites. 1. Secondary structure formation by peptides corresponding to the G-and H-helices of myoglobin. Biochemistry, 32, 6337–6347 (1993).

    Article  PubMed  CAS  Google Scholar 

  52. H.-C. Shin, G. Merutka, J.P. Waltho, P.E. Wright and H.J. Dyson, Peptide models of protein folding initiation sites. 2. The G-H turn region of myoglobin acts as a helix stop signal. Biochemistry, 32, 6348–6355 (1993).

    Article  PubMed  CAS  Google Scholar 

  53. H.-C. Shin, G. Merutka, J.P. Waltho, L.L. Tennant, H.J. Dyson and P.E. Wright, Peptide models of protein folding initiation sites. 3. The G-H helical hairpin of myoglobin. Biochemistry, 32, 6356–6364 (1993).

    Article  PubMed  CAS  Google Scholar 

  54. K.R. Shoemaker, P.S. Kim, E.J. York, J.M. Stewart and R.L. Baldwin, Tests of the helix dipole model for stabilization of α-helices. Nature, 326, 563–567 (1987).

    Article  PubMed  CAS  Google Scholar 

  55. K.R. Shoemaker, R. Fairman, P.S. Kim, E.J. York, J.M. Stewart and R.L. Baldwin, The C-peptide helix from ribonuclease A considered as an autonomous folding unit. Cold Spring Harbor Symp. Quant. Biol., LII, 391–398 (1987).

    Article  Google Scholar 

  56. J. Skolnick and A. Kolinski, Simulations of the folding of a globular protein. Science, 250, 1121–1125 (1990).

    Article  PubMed  CAS  Google Scholar 

  57. J. Skolnick and A. Kolinski, Dynamic Monte Carlo simulation of a new lattice model of globular protein folding, structure and dynamics. J. Mol. Biol., 221, 499–531 (1991).

    Article  PubMed  CAS  Google Scholar 

  58. P.E. Wright, H.J. Dyson, V.A. Feher, L.L. Tennant, J.P. Waltho, R.A. Lerner and D.A. Case, Folding of peptide fragments of proteins in aqueous solution, in “Frontiers of NMR in Molecular Biology”, D. Live, I.M. Armitage and D. Patel, ed., Alan R. Liss, Inc., New York. (1990) pp. 1–13.

    Google Scholar 

  59. D.J. Tobias and C.L. Brooks, Thermodynamics and mechanism of α-helix initiation in alanine and valine peptides. Biochemistry, 30, 6059–6070 (1991).

    Article  PubMed  CAS  Google Scholar 

  60. A.L. Cummings and E.M. Eyring, Helix-coil transition kinetics in aqueous poly (α, L-glutamic acid). Biopolymers, 14, 2107–2114 (1975).

    Article  CAS  Google Scholar 

  61. R. Lumry, R. Legare and W.G. Miller, The dynamics of the helix-coil transition in poly-α, L-glutamic acid. Biopolymers, 2, 489–500 (1964).

    Article  CAS  Google Scholar 

  62. T.E. Creighton, Stability of folded conformations. Curr. Opin. Struct. Biol., 1, 5–16 (1991).

    Article  CAS  Google Scholar 

  63. G.A. Elöve, A.F. Chaffotte, H. Roder and M.E. Goldberg, Early steps in cytochrome c folding probed by time-resolved circular dichroism and fluorescence spectroscopy. Biochemistry, 31, 6876–6883 (1992).

    Article  PubMed  Google Scholar 

  64. P. Varley, A.M. Gronenborn, H. Christensen, P.T. Wingfield, R.H. Pain and G.M. Clore, Kinetics of folding of the all-β sheet protein interleukin-lβ. Science, 260, 1110–1113 (1993).

    Article  PubMed  CAS  Google Scholar 

  65. L.L. Shen and J. Hermans Jr, Kinetics of conformation change of sperm-whale myoglobin II Characterization of the rapidly and slowly formed denatured species. Biochemistry, 11, 1842–1849 (1972).

    Article  PubMed  CAS  Google Scholar 

  66. M. Ikeguchi, K. Kuwajima, M. Mitani and S. Sugai, Evidence for identity between the equilibrium unfolding intermediate and a transient folding intermediate: a comparative study of the folding reaction of α-lactoalbumin and lysozyme. Biochemistry, 25, 6965–6972 (1986).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular Biology, The Scripps Research Institute, 10666 North Torrey Pines Road, La Jolla, California, 92037, USA

    Patricia A. Jennings, H. Jane Dyson & Peter E. Wright

Authors
  1. Patricia A. Jennings
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H. Jane Dyson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter E. Wright
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Stanford University, Stanford, California, USA

    Sebastian Doniach

Rights and permissions

Reprints and permissions

Copyright information

© 1994 Springer Science+Business Media New York

About this chapter

Cite this chapter

Jennings, P.A., Dyson, H.J., Wright, P.E. (1994). The Folding Pathway of Apomyoglobin. In: Doniach, S. (eds) Statistical Mechanics, Protein Structure, and Protein Substrate Interactions. NATO ASI Series, vol 325. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-1349-4_2

Download citation

  • DOI: https://doi.org/10.1007/978-1-4899-1349-4_2

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4899-1351-7

  • Online ISBN: 978-1-4899-1349-4

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation