Protein Engineering, Vol. 15, No. 6, 513-520,
June 2002
© 2002 Oxford University Press
Lipid-interacting properties of the N-terminal domain of human apolipoprotein C-III
1 INSERM U447, IBL, 59021 Lille Cedex, France, 2 Centre de Biophysique Moléculaire Numérique, FSAGX, 5030 Gembloux, Belgium, 3 Division of Cardiovascular Genetics, Department of Medicine, Royal and Free University College Medical School, London WC1E 6JJ, UK and 4 INSERM U410, Faculté X.Bichat,75870 Paris Cedex 18, France
The lipid-interacting properties of the N-terminal domain of human apolipoprotein C-III (apo C-III) were investigated. By molecular modeling, we predicted that the 6–20 fragment of apo C-III is obliquely orientated at the lipid/water interface owing to an asymmetric distribution of the hydrophobic residues when helical. This is characteristic of `tilted peptides' originally discovered in viral fusion proteins and later in various proteins including some involved in lipoprotein metabolism. Since most tilted peptides were shown to induce liposome fusion in vitro, the fusogenic capacity of the 6–20 fragment of apo C-III was tested on unilamellar liposomes and compared with the well characterized SIV fusion peptide. Mutants were designed by molecular modeling to assess the role of the hydrophobicity gradient in the fusion. FTIR spectroscopy confirmed the predominantly helical conformation of the peptides in TFE solution and also in lipid–peptide complexes. Lipid-mixing experiments showed that the apo C-III (6–20) peptide is able to increase the fluorescence of a lipophilic fluorescent probe. The vesicle fusion was confirmed by core-mixing and leakage assays. The hydrophobicity gradient plays a key role in the fusion process because the mutant with no hydrophobic asymmetry but the same mean hydrophobicity as the wild type does not induce significant lipid fusion. The apo C-III (6–20) fragment is, however, less fusogenic than the SIV peptide, in agreement with their respective mean hydrophobicity. Since lipid fusion should not be the physiological function of the N-terminal domain of apo CIII, we suggest that its peculiar distribution of hydrophobic residues is important for the lipid-binding properties of apo C-III and should be involved in apolipoprotein and lipid exchanges crucial for triglyceride metabolism.
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