title: Association of a model class A (apolipoprotein) amphipathic alpha helical peptide with lipid: high resolution NMR studies of peptide.lipid discoidal complexes.
abstract: Class A amphipathic helical peptides have been shown to mimic apolipoprotein A-I, the major protein component of high density lipoproteins and have been shown to inhibit atherosclerosis in several dyslipidemic mouse models. Previously we reported the NMR structure of Ac-18A-NH2, the base-line model class A amphipathic helical peptide in a 50% (v/v) trifluoroethanol-d3/water mixture, a membrane-mimic environment (Mishra, V. K., Palgunachari, M. N., Anantharamaiah, G. M., Jones, M. K., Segrest, J. P., and Krishna, N. R. (2001) Peptides 22, 567-573). The peptide Ac-18A-NH2 forms discoidal nascent high density lipoprotein-like particles with 1,2-dimyristoyl-sn-glycero-3-phosphocholine. Because subtle structural changes in the peptide.lipid complexes have been shown to be responsible for their antiatherogenic properties, we undertook high resolution NMR studies to deduce detailed structure of recombinant peptide.1,2-dimyristoyl-sn-glycero-3-phosphocholine complexes. The peptide adopts a well defined amphipathic alpha helical structure in association with the lipid at a 1:1 peptide:lipid weight ratio. Nuclear Overhauser effect spectroscopy revealed a number of intermolecular close contacts between the aromatic residues in the hydrophobic face of the helix and the lipid acyl chain protons. The pattern of observed peptide-lipid nuclear Overhauser effects is consistent with a parallel orientation of the amphipathic alpha helix, with respect to the plane of the lipid bilayer, on the edge of the disc (the belt model). Based on the results of chemical cross-linking and molecular modeling, we propose that peptide helices are arranged in a head to tail fashion to cover the edge of the disc. This arrangement of peptides is also consistent with the pKa values of the Lys residues determined previously. Taken together, these results provide for the first time a high resolution structural view of the peptide.lipid discoidal complexes formed by a class A amphipathic alpha helical peptide.
authors.affiliation: The Atherosclerosis Research Unit, Department of Medicine, and Department of Biochemistry and Molecular Genetics and Comprehensive Cancer Center, University of Alabama at Birmingham Medical Center, Birmingham, Alabama 35294, USA.
authors.forename: Vinod K
authors.initials: VK
authors.lastname: Mishra
authors.forename: G M
authors.initials: GM
authors.lastname: Anantharamaiah
authors.forename: Jere P
authors.initials: JP
authors.lastname: Segrest
authors.forename: Mayakonda N
authors.initials: MN
authors.lastname: Palgunachari
authors.forename: Manjula
authors.initials: M
authors.lastname: Chaddha
authors.forename: S W Simon
authors.initials: SW
authors.lastname: Sham
authors.forename: N Rama
authors.initials: NR
authors.lastname: Krishna
mesh_terms: D000595:Amino Acid Sequence; D001054:Apolipoproteins A / Q000737:chemistry / Q000378:metabolism*; D002850:Chromatography, Gel; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism*; D017433:Protein Structure, Secondary
chemical_list: D001054:Apolipoproteins A; D010455:Peptides; C080383:peptide 18A; D004134:Dimyristoylphosphatidylcholine