| Title | Structure and dynamics of human apolipoprotein CIII. | | Author(s) | Gangabadage CS, Zdunek J, Tessari M, Nilsson S, Olivecrona G, Wijmenga SS | | Institution | Biophysical Chemistry, Institute of Molecules and Materials, Radboud University, Nijmegen 6525 ED. | | Source | J Biol Chem 2008 Apr 11. | | Abstract | Human apolipoprotein CIII (apoCIII) is a surface component of chylomicrons, very-low density lipoproteins and high-density lipoproteins. ApoCIII inhibits lipoprotein lipase (LPL) as well as binding of lipoproteins to cell surface heparan sulfate proteoglycans and receptors. High levels of apoCIII are often correlated with elevated levels of blood lipids (hypertriglyceridemia). Here, we report the three-dimensional NMR structure and dynamics of human apoCIII in complex with SDS micelles, mimicking its natural lipid-bound state. Thanks to residual dipolar coupling data the first detailed view is obtained of the structure and dynamics of an intact apolipoprotein in its lipid-bound state. ApoCIII wraps around the micelle surface as a necklace of six circa 10-residue-amphipathic helices, which are curved and connected via semi-flexible hinges. Three positively charged (Lys) residues line the polar faces of helices 1 and 2. Interestingly, their 3D conformation is similar to that of the LDL receptor binding motifs of apoE/B and the receptor associated protein (RAP). At the C-terminal side of apoCIII, an array of negatively charged residues lines the polar faces of helices 4, 5 and adjacent flexible loop. Sequence comparison shows that this asymmetric charge distribution along the solvent-exposed face of apoCIII as well as other structural features, are conserved among mammals. This structure provides a template for exploration of molecular mechanisms by which human apoCIII inhibits LPL and receptor binding. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 18408013 |
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