title: Modulation of apolipoprotein E structure by domain interaction: differences in lipid-bound and lipid-free forms.
abstract: Interaction of the amino- and carboxyl-terminal domains in apolipoprotein (apo) E, referred to as domain interaction, is predicted to be more pronounced in apoE4 than in apoE3 and to underlie the association of apoE4 with Alzheimer and cardiovascular diseases. However, direct physical proof for the domain interaction concept is lacking. To address this issue, fluorescence resonance energy transfer and electron paramagnetic resonance spectroscopy were used to probe the spatial proximity of the two domains of apoE. Both methods demonstrated that the two domains are closer in both lipid-free and phospholipid-bound apoE4 than in apoE3 as a result of domain interaction. In addition, as shown by electron paramagnetic resonance, the domains of apoE4 move apart to resemble more closely the distance in apoE3 when the isoforms are bound to triglyceride-rich emulsion particles. These results demonstrate that domain interaction is a structural property of apoE4 and that apoE adopts different conformations when complexed to different lipids.
authors.affiliation: Gladstone Institutes of Cardiovascular and Neurological Diseases, San Francisco, California 94158, USA.
authors.forename: Danny M
authors.initials: DM
authors.lastname: Hatters
authors.forename: Madhu S
authors.initials: MS
authors.lastname: Budamagunta
authors.forename: John C
authors.initials: JC
authors.lastname: Voss
authors.forename: Karl H
authors.initials: KH
authors.lastname: Weisgraber
mesh_terms: D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000737:chemistry* / Q000502:physiology*; D004578:Electron Spin Resonance Spectroscopy; D031541:Fluorescence Resonance Energy Transfer; D008055:Lipids; D008853:Microscopy; D008961:Models, Structural; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D011487:Protein Conformation; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary
chemical_list: D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D008055:Lipids; D020033:Protein Isoforms