title: The "beta-clasp" model of apolipoprotein A-I--a lipid-free solution structure determined by electron paramagnetic resonance spectroscopy.
abstract: Apolipoprotein A-I (apoA-I) is the major protein component of high density lipoproteins (HDL) and plays a central role in cholesterol metabolism. The lipid-free/lipid-poor form of apoA-I is the preferred substrate for the ATP-binding cassette transporter A1 (ABCA1). The interaction of apoA-I with ABCA1 leads to the formation of cholesterol laden high density lipoprotein (HDL) particles, a key step in reverse cholesterol transport and the maintenance of cholesterol homeostasis. Knowledge of the structure of lipid-free apoA-I is essential to understanding its critical interaction with ABCA1 and the molecular mechanisms underlying HDL biogenesis. We therefore examined the structure of lipid-free apoA-I by electron paramagnetic resonance spectroscopy (EPR). Through site directed spin label EPR, we mapped the secondary structure of apoA-I and identified sites of spin coupling as residues 26, 44, 64, 167, 217 and 226. We capitalize on the fact that lipid-free apoA-I self-associates in an anti-parallel manner in solution. We employed these sites of spin coupling to define the central plane in the dimeric apoA-I complex. Applying both the constraints of dipolar coupling with the EPR-derived pattern of solvent accessibility, we assembled the secondary structure into a tertiary context, providing a solution structure for lipid-free apoA-I. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).
authors.affiliation: Department of Experimental Medical Science, Lund University, S-221 84 Lund, Sweden.
authors.forename: Jens O
authors.initials: JO
authors.lastname: Lagerstedt
authors.forename: Madhu S
authors.initials: MS
authors.lastname: Budamagunta
authors.forename: Grace S
authors.initials: GS
authors.lastname: Liu
authors.forename: Nicole C
authors.initials: NC
authors.lastname: DeValle
authors.forename: John C
authors.initials: JC
authors.lastname: Voss
authors.forename: Michael N
authors.initials: MN
authors.lastname: Oda
mesh_terms: D016632:Apolipoprotein A-I / Q000737:chemistry*; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D013194:Staining and Labeling
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I