Folding of β-sheet membrane proteins

A hydrophobic hexapeptide model

William C. Wimley, Kalina A Hristova, Alexey S. Ladokhin, Loraine Silvestro, Paul H. Axelsen, Stephen H. White

Research output: Contribution to journalArticle

Abstract

Beta-sheets, in the form of the β-barrel folding motif, are found in several constitutive membrane proteins (porins) and in several microbial toxins that assemble on membranes to form oligomeric transmembrane channels. We report here a first step towards understanding the principles of β-sheet formation in membranes. In particular, we describe the properties of a simple hydrophobic hexapeptide, acetyl-Trp-leu5 (AcWL5), that assembles cooperatively into β-sheet aggregates upon partitioning into lipid bilayer membranes from the aqueous phase where the peptide is strictly monomeric and random coil. The aggregates, containing 10 to 20 monomers, undergo a relatively sharp and reversible thermal unfolding at ~ 60°C. No pores are formed by the aggregates, but they do induce graded leakage of vesicle contents at very high peptide to lipid ratios. Because β-sheet structure is not observed when the peptide is dissolved in n-octanol, trifluoroethanol or sodium dodecyl sulfate micelles, aggregation into β-sheets appears to be an exclusive property of the peptide in the bilayer membrane interface. This is an expected consequence of the hypothesis that a reduction in the free energy of partitioning of peptide bonds caused by hydrogen bonding drives secondary structure formation in membrane interfaces. But, other features of interfacial partitioning, such as side-chain interactions and reduction of dimensionality, must also contribute. We estimate from our partitioning data that the free energy reduction per residue for aggregation is about 0.5 kcal mol-1. Although modest, its aggregate effect on the free energy of assembling β-sheet proteins can be huge. This surprising finding, that a simple hydrophobic hexapeptide readily assembles into oligomeric β-sheets in membranes, reveals the potent ability of membranes to promote secondary structure in peptides, and shows that the formation of β-sheets in membranes is more facile than expected. Furthermore, it provides a basis for understanding the observation that membranes promote self-association of β-amyloid peptides. AcWL5, and related peptides thus provide a good starting point for designing peptide models for exploring the principles of β-sheet formation in membranes.

Original languageEnglish (US)
Pages (from-to)1091-1110
Number of pages20
JournalJournal of Molecular Biology
Volume277
Issue number5
DOIs
StatePublished - Apr 17 1998
Externally publishedYes

Fingerprint

Staphylococcal Protein A
Membrane Proteins
Membranes
Peptides
Trifluoroethanol
1-Octanol
Porins
Lipid Bilayers
Micelles
Hydrogen Bonding
Amyloid
Sodium Dodecyl Sulfate
Hot Temperature
Lipids

Keywords

  • β-amyloid peptides
  • β-barrel proteins
  • Lipid bilayers
  • Partitioning of peptides into membranes
  • Thermal unfolding

ASJC Scopus subject areas

  • Virology

Cite this

Wimley, W. C., Hristova, K. A., Ladokhin, A. S., Silvestro, L., Axelsen, P. H., & White, S. H. (1998). Folding of β-sheet membrane proteins: A hydrophobic hexapeptide model. Journal of Molecular Biology, 277(5), 1091-1110. https://doi.org/10.1006/jmbi.1998.1640

Folding of β-sheet membrane proteins : A hydrophobic hexapeptide model. / Wimley, William C.; Hristova, Kalina A; Ladokhin, Alexey S.; Silvestro, Loraine; Axelsen, Paul H.; White, Stephen H.

In: Journal of Molecular Biology, Vol. 277, No. 5, 17.04.1998, p. 1091-1110.

Research output: Contribution to journalArticle

Wimley, WC, Hristova, KA, Ladokhin, AS, Silvestro, L, Axelsen, PH & White, SH 1998, 'Folding of β-sheet membrane proteins: A hydrophobic hexapeptide model', Journal of Molecular Biology, vol. 277, no. 5, pp. 1091-1110. https://doi.org/10.1006/jmbi.1998.1640
Wimley, William C. ; Hristova, Kalina A ; Ladokhin, Alexey S. ; Silvestro, Loraine ; Axelsen, Paul H. ; White, Stephen H. / Folding of β-sheet membrane proteins : A hydrophobic hexapeptide model. In: Journal of Molecular Biology. 1998 ; Vol. 277, No. 5. pp. 1091-1110.
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AB - Beta-sheets, in the form of the β-barrel folding motif, are found in several constitutive membrane proteins (porins) and in several microbial toxins that assemble on membranes to form oligomeric transmembrane channels. We report here a first step towards understanding the principles of β-sheet formation in membranes. In particular, we describe the properties of a simple hydrophobic hexapeptide, acetyl-Trp-leu5 (AcWL5), that assembles cooperatively into β-sheet aggregates upon partitioning into lipid bilayer membranes from the aqueous phase where the peptide is strictly monomeric and random coil. The aggregates, containing 10 to 20 monomers, undergo a relatively sharp and reversible thermal unfolding at ~ 60°C. No pores are formed by the aggregates, but they do induce graded leakage of vesicle contents at very high peptide to lipid ratios. Because β-sheet structure is not observed when the peptide is dissolved in n-octanol, trifluoroethanol or sodium dodecyl sulfate micelles, aggregation into β-sheets appears to be an exclusive property of the peptide in the bilayer membrane interface. This is an expected consequence of the hypothesis that a reduction in the free energy of partitioning of peptide bonds caused by hydrogen bonding drives secondary structure formation in membrane interfaces. But, other features of interfacial partitioning, such as side-chain interactions and reduction of dimensionality, must also contribute. We estimate from our partitioning data that the free energy reduction per residue for aggregation is about 0.5 kcal mol-1. Although modest, its aggregate effect on the free energy of assembling β-sheet proteins can be huge. This surprising finding, that a simple hydrophobic hexapeptide readily assembles into oligomeric β-sheets in membranes, reveals the potent ability of membranes to promote secondary structure in peptides, and shows that the formation of β-sheets in membranes is more facile than expected. Furthermore, it provides a basis for understanding the observation that membranes promote self-association of β-amyloid peptides. AcWL5, and related peptides thus provide a good starting point for designing peptide models for exploring the principles of β-sheet formation in membranes.

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