Lipid-bound structure of an apolipoprotein E-derived peptide.
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.
Raussens
Vincent
V
Protein Engineering Network Centres of Excellence and Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
Slupsky
Carolyn M
CM
Sykes
Brian D
BD
Ryan
Robert O
RO
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
D001057:Apolipoproteins E; D008024:Ligands; D008823:Micelles; D010455:Peptides; D011522:Protons; D011973:Receptors, LDL; D014270:Trifluoroethanol