title: Structures of apolipoprotein A-II and a lipid-surrogate complex provide insights into apolipoprotein-lipid interactions.
abstract: Apolipoproteins A-I and A-II form the major protein constituents of high-density lipid particles (HDL), the concentration of which is inversely correlated with the frequency of heart disease in humans. Although the physiological role of apolipoprotein A-II is unclear, evidence for its involvement in free fatty acid metabolism in mice has recently been obtained. Currently, the best characterized activity of apolipoprotein A-II is its potent antagonism of the anti-atherogenic and anti-inflammatory activities of apolipoprotein A-I, probably due to its competition with the latter for lipid acyl side chains in HDL. Many interactions of apolipoprotein A-I with enzymes and proteins involved in reverse cholesterol transport and HDL maturation are mediated by lipid-bound protein. The structural bases of interaction with lipids are expected to be common to exchangeable apolipoproteins and attributable to amphipathic alpha-helices present in each of them. Thus, characterization of apolipoprotein-lipid interactions in any apolipoprotein is likely to provide information that is applicable to the entire class. We report structures of human apolipoprotein A-II and its complex with beta-octyl glucoside, a widely used lipid surrogate. The former shows that disulfide-linked dimers of apolipoprotein A-II form amphipathic alpha-helices which aggregate into tetramers. Dramatic changes, observed in the presence of beta-octyl glucoside, might provide clues to the structural basis for its antagonism of apolipoprotein A-I. Additionally, excursions of individual molecules of apolipoprotein A-II from a common helical architecture in both structures indicate that lipid-bound apolipoproteins are likely to have an ensemble of related conformations. These structures provide the first experimental paradigm for description of apolipoprotein-lipid interactions at the atomic level.
authors.affiliation: Center for Biophysical Sciences and Engineering, University of Alabama at Birmingham, 1530 3rd Avenue South, Birmingham, AL 35294, USA.
authors.forename: M Suresh
authors.initials: MS
authors.lastname: Kumar
authors.forename: M
authors.initials: M
authors.lastname: Carson
authors.forename: M Mahmood
authors.initials: MM
authors.lastname: Hussain
authors.forename: H M Krishna
authors.initials: HM
authors.lastname: Murthy
mesh_terms: D000595:Amino Acid Sequence; D016633:Apolipoprotein A-II / Q000737:chemistry*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D019281:Dimerization; D005960:Glucosides / Q000737:chemistry*; D006801:Humans; D008075:Lipoproteins, HDL / Q000737:chemistry*; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D055672:Static Electricity; D013329:Structure-Activity Relationship
chemical_list: D016633:Apolipoprotein A-II; D005960:Glucosides; D008075:Lipoproteins, HDL; D046911:Macromolecular Substances; C018619:octyl-beta-D-glucoside