TY - JOUR
T1 - Folding of β-sheet membrane proteins
T2 - A hydrophobic hexapeptide model
AU - Wimley, William C.
AU - Hristova, Kalina
AU - Ladokhin, Alexey S.
AU - Silvestro, Loraine
AU - Axelsen, Paul H.
AU - White, Stephen H.
N1 - Funding Information:
The research was supported in part by grants from the National Institutes of Health, GM-46823 (to S.H.W.), AI-31696 and AI-22931 (to Michael E. Selsted), and GM54617 (to P.H.A.) and by a grant-in-aid to P.H.A. from the American Heart Association, SE Pennsylvania Affiliate. We thank Dr Mark Sansom for providing the coordinates of alanine β-barrel models.
PY - 1998/4/17
Y1 - 1998/4/17
N2 - 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.
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.
KW - Lipid bilayers
KW - Partitioning of peptides into membranes
KW - Thermal unfolding
KW - β-amyloid peptides
KW - β-barrel proteins
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U2 - 10.1006/jmbi.1998.1640
DO - 10.1006/jmbi.1998.1640
M3 - Article
C2 - 9571025
AN - SCOPUS:0032540234
SN - 0022-2836
VL - 277
SP - 1091
EP - 1110
JO - Journal of molecular biology
JF - Journal of molecular biology
IS - 5
ER -