title: Lipid-bound structure of an apolipoprotein E-derived peptide.
abstract: Apolipoprotein (apo) E regulates plasma lipid homeostasis through its ability to interact with the low density lipoprotein (LDL) receptor family. Whereas apoE is not a ligand for receptor binding in buffer alone, interaction with lipid confers receptor recognition properties. To investigate the nature of proposed lipid binding-induced conformational changes in apoE, we employed multidimensional heteronuclear NMR spectroscopy to determine the structure of an LDL receptor-active, 58-residue peptide comprising residues 126-183 of apoE in association with the micelle-forming lipid dodecylphosphocholine (DPC). In the presence of 34 mm DPC the peptide forms a continuous amphipathic helix from Glu131 to Arg178. NMR relaxation studies of DPC-bound apoE-(126-183), in contrast to apoE-(126-183) in the presence of TFE, are consistent with an isotropically tumbling peptide in solution giving a global correlation time of approximately 12.5 ns. These data indicate that the helical peptide is curved and constrained by a lipid micelle consisting of approximately 48 DPC molecules. Although the peptide behaves as if it were tumbling isotropically, spectral density analysis reveals that residues 150-183 have more motional freedom than residues 134-149. These molecular and dynamic features are discussed further to provide insight into the structural basis for the interaction between apoE and the ligand binding repeats of the LDL receptor.
authors.affiliation: Protein Engineering Network Centres of Excellence and Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
authors.forename: Vincent
authors.initials: V
authors.lastname: Raussens
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Slupsky
authors.forename: Brian D
authors.initials: BD
authors.lastname: Sykes
authors.forename: Robert O
authors.initials: RO
authors.lastname: Ryan
mesh_terms: D000595:Amino Acid Sequence; D001057:Apolipoproteins E / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D050356:Lipid Metabolism; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D011522:Protons; D011973:Receptors, LDL / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013997:Time Factors; D014270:Trifluoroethanol / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; D008024:Ligands; D008823:Micelles; D010455:Peptides; D011522:Protons; D011973:Receptors, LDL; D014270:Trifluoroethanol