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The hydrophobic-staple motif and a role for loop-residues in α-helix stability and protein folding

Nature Structural Biology volume 2, pages 380–385 (1995)Cite this article

Abstract

A recurrent local structural motif is described at the amino terminus of α-helices, that consists of a specific hydrophobic interaction between a residue located before the N-cap, with a residue within the helix (i,i+5 interaction). NMR and CD analysis of designed peptides demonstrate its presence in aqueous solution, its contribution to α-helix stability and its role in defining the α-helix N terminus limit. Comparison between the N-terminal structures of the peptide and those in proteins with the same fingerprint sequence, shows striking similarities. The change in the polypeptide chain direction produced by the motif suggests an important role in protein folding for residues located in polypeptide segments between secondary structure elements.

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References

  1. Anfinsen, C.B. The kinetics of formation of of native ribonuclease during oxydation of the reduced polypeptide chain. Science 181, 223–230 (1973).

    CAS  Google Scholar 

  2. Chreighton, T.E. Protein folding. Biochem. J. 270, 1–16 (1990).

    Article  Google Scholar 

  3. Karplus, M. & Weaver, D.L. Protein folding dynamics. Biopolymers 18, 1421–1437 (1979).

    Article  CAS  Google Scholar 

  4. Dill, K.A., Fiebig, K.M. & Chan, H.S. Cooperativity in protein-folding kinetics. Proc. natn. Acad. Sci. U.S.A. 90, 1942–1496, (1993).

    Article  CAS  Google Scholar 

  5. Harper, J. & Rose, G.D. Helix stop signals in proteins and peptides: the capping box. Biochemistry 32, 7605–7609 (1993).

    Article  CAS  Google Scholar 

  6. Richardson, J.S. & Richardson, D.C. Amino acid preferences for specific locations at the ends of α-helices. Science 240, 1648–1652 (1988).

    Article  CAS  Google Scholar 

  7. Dasgupta, S. & Bell, J.A. Design of helix ends. Int. J. Peptide Res. 41, 499–511 (1993).

    Article  CAS  Google Scholar 

  8. Seale, J.W., Srinivasan, R. & Rose, G.D. Sequence determinants of the capping-box, a stabilizing motif at the N-termini of α-helices. Prot. Sci. 3, 1741–1745, (1994).

    Article  CAS  Google Scholar 

  9. Sippl, M. Calculation of conformational ensembles from potentials of mean force. An approach to the knowledge-based prediction of local structures in globular proteins. J. molec. Biol. 213, 859–883 (1990).

    Article  CAS  Google Scholar 

  10. Jiméenez, M.A., Nieto, J.L., Herranz, J., Rico, M. & Santoro, J. 1H NMR and CD evidence of the folding of the isolated ribonuclease 50–61 fragment. FEBS Letts 221, 320–324 (1987).

    Article  Google Scholar 

  11. Wishart, D.S., Sykes, B.D. & Richards, F.M. Relationship between nuclear magnetic resonance chemical shifts and protein secondary structure. J. molec. Biol. 222, 333–344 (1991).

    Article  Google Scholar 

  12. Lyu, P.C., Zhou, H.X., Jelveh, N. Wemmer, D.E. & Kallenbach, N.R. Position-dependent stabilizing effects in α-helices: N-terminal capping in synthetic model peptides. J. Am. chem. Soc. 114, 6560–6562 (1992).

    Article  CAS  Google Scholar 

  13. Wüthrich, K. NMR of proteins and nucleic acids. (John Wiley & sons, New York, 1986).

    Book  Google Scholar 

  14. Lyu, P.C., Liff, M.I., Marky, L.A. & Kallenbach, N.R. Side chain contributions to the stability of α-helical structures in peptides. Science 250, 669–673 (1990).

    Article  CAS  Google Scholar 

  15. O'Neil, K.T. & DeGrado, W.F. A thermodynamic scale for the helix-forming tendencies of the commonly occurring amino acids. Science 250, 646–650 (1990).

    Article  CAS  Google Scholar 

  16. Serrano, L., Neira, J.L., Sancho, J. & Fersht, A.R. Effect of alanine versus glycine in α-helices on protein stability. Nature 356, 453–455 (1992).

    Article  CAS  Google Scholar 

  17. Horovitz, A., Matthews, J. & Fersht, A.R. α-helix stability in proteins. II. Factors that influence stability at an internal position. J. molec. Biol. 227, 560–568 (1992).

    Article  CAS  Google Scholar 

  18. Blaber, M., Zang, X. & Matthews, B. Structural basis of amino acid α-helix propensity. Science 260, 1637–1640 (1993).

    Article  CAS  Google Scholar 

  19. Chakrabartty, T. Kortemme & Baldwin R.L. Large differences in the helix propensities of alanine and glycine. Prot. Sci. 3, 843–847 (1994).

    Article  CAS  Google Scholar 

  20. Jiménez, M.A., Muñoz, V., Rico, M. & Serrano, L. Helix stop and start signals in peptides and proteins: The capping box does not necessarily prevent helix elongation. J. molec. Biol. 242, 487–496(1994).

    PubMed  Google Scholar 

  21. Muñoz, V. & Serrano, L. Elucidating the folding problem of helical peptides using empirical parameters. Nature struct. Biol. 1, 399–409 (1994).

    Article  Google Scholar 

  22. Muñoz, V. & Serrano, L. Elucidating the folding problem of helical peptides using empirical parameters, II: helix macrodipole effects and rational modification of the helical content of natural peptides. J. molec. Biol. 245, 275–296. (1995).

    Article  Google Scholar 

  23. Muñoz, V. & Serrano, L. Elucidating the folding problem of helical peptides using empirical parameters, III: Temperature and pH dependence. J. molec. Biol. 245, 297–308. (1995).

    Article  Google Scholar 

  24. Hobohm, U., Scharf, M., Schneider, R. & Sander, C. Selection of representative protein datasets. Prot. Sci. 1, 409 (1992).

    Article  CAS  Google Scholar 

  25. Muñoz, V. & Serrano, L. Intrinsic secondary structure propensities of the amino acids, using statistical phi-psi matrices: comparison with experimental scales. Prot. Struct. Funct. Genet. 20, 301–311 (1994).

    Article  Google Scholar 

  26. Vriend, G. WHATIF: A molecular modeling and drug design program. J. molec. Graph. 8, 52–56 (1990).

    Article  CAS  Google Scholar 

  27. Kabsch, W. & Sander, C. Dictionary of protein secondary structure: pattern of recognition of hydrogen-bonded and geometrical features. Biopolymers 22, 2577–2637 (1983).

    Article  CAS  Google Scholar 

  28. P. Güntert, W., Braun, K., Wüthrich Improved efficiency of protein structure calculations from NMR using the program DIANA with redundant dihedral angle constraints. J. molec. Biol. 217, 517–530 (1991).

    Article  Google Scholar 

  29. Chen, Y.H., Yang, J.T. & Chow, K.H. Determination of the helix and β form of proteins in aqueous solution by circular dichroism. Biochemistry 13, 3350–3359 (1974).

    Article  CAS  Google Scholar 

  30. Bruch, M.D., Dhingra, M.M. & Gierasch, L.M. Side chain backbone hydrogen bonding contributes to helix stability in peptides derived from an α-helical region of carboxypeptidase A Prot. Struct. Func. Genet. 10, 130 (1991).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. EMBL, Postfach 102209, Meyerhofstrasse 1, 69012, Heidelberg, Germany

    Victor Muñoz, Francisco J. Blanco & Luis Serrano

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  1. Victor Muñoz
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  2. Francisco J. Blanco
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  3. Luis Serrano
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Muñoz, V., Blanco, F. & Serrano, L. The hydrophobic-staple motif and a role for loop-residues in α-helix stability and protein folding. Nat Struct Mol Biol 2, 380–385 (1995). https://doi.org/10.1038/nsb0595-380

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