NMR structure and dynamics of a receptor-active apolipoprotein E peptide.
Apolipoprotein E (apoE) is important in lipid metabolism due to its interaction with members of the low density lipoprotein (LDL) receptor family. ApoE is able to interact with the LDL receptor only when it is bound to lipid particles. To address structural aspects of this phenomenon, a receptor-active apoE peptide, encompassing the receptor-binding region of the protein, was studied by NMR in the presence of the lipid-mimicking agent trifluoroethanol. In 50% trifluoroethanol, apoE-(126-183) forms a continuous amphipathic alpha-helix over residues Thr(130)-Glu(179). Detailed NMR relaxation analysis indicates a high degree of plasticity for the residues surrounding 149-159. This intrinsic flexibility imposes a curvature to the peptide that may be important in terms of interaction of apoE with various sized lipid particles and the LDL receptor. Residues 165-179 of apoE may act as a molecular switch whereby these residues are unstructured in the absence of lipids and prevent interaction with the LDL receptor. In the presence of lipids, these residues become helical resulting in a receptor-active conformation of the protein. Furthermore, the electrostatic characteristics and geometric features of apoE-(126-183) suggest that apoE binds to the LDL receptor by interacting with more than one of the receptor ligand-binding repeats.
Raussens
Vincent
V
Protein Engineering Network Centres of Excellence, 713 Heritage Medical Research Center, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
Slupsky
Carolyn M
CM
Ryan
Robert O
RO
Sykes
Brian D
BD
D000595:Amino Acid Sequence; D001057:Apolipoproteins E / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008077:Lipoproteins, LDL / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011973:Receptors, LDL / Q000378:metabolism; D014270:Trifluoroethanol / Q000494:pharmacology
D001057:Apolipoproteins E; D008024:Ligands; D008077:Lipoproteins, LDL; D010455:Peptides; D011973:Receptors, LDL; D014270:Trifluoroethanol