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J. Biol. Chem., Vol. 283, Issue 25, 17416-17427, June 20, 2008

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Structure and Dynamics of Human Apolipoprotein CIII^*

Chinthaka Saneth Gangabadage, Janusz Zdunek^¶, Marco Tessari, Solveig Nilsson^||, Gunilla Olivecrona^||, and Sybren Sipke Wijmenga¹

From the Department of Physical Chemistry-Biophysical Chemistry, Radboud University of Nijmegen, Toernooiveld 1, 6525 ED, Nijmegen, The Netherlands, the Department of Chemistry, University of Ruhuna, Matara, Sri Lanka, and the Departments of ^¶Medical Biochemistry and Biophysics and ^||Medical Biosciences/Physiological Chemistry, SE-90187, Umeå University, Umeå, Sweden

Human apolipoprotein CIII (apoCIII) is a surface component of chylomicrons, very low density lipoproteins, and high density lipoproteins. ApoCIII inhibits lipoprotein lipase 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 apo-CIII 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 10-residue amphipathic helices, which are curved and connected via semiflexible hinges. Three positively charged (Lys) residues line the polar faces of helices 1 and 2. Interestingly, their three-dimensional conformation is similar to that of the low density lipoprotein receptor binding motifs of apoE/B and the receptor-associated protein. At the C-terminal side of apoCIII, an array of negatively charged residues lines the polar faces of helices 4 and 5 and the 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 lipoprotein lipase and receptor binding.

Received for publication, January 29, 2008 , and in revised form, March 25, 2008.

The atomic coordinates and structure factors (code 2jq3) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

The ¹H and ¹⁵N chemical shifts have been deposited in the BioMagResBank data base (http://www.bmrb.wisc.edu) under accession number 15268.

^* This work was supported by NatuurWetenschappelijk Onderzoek Nederland, The Netherlands (to S. W.), the Swedish Medical Research Council, and the Biotechnology Fund at Umeå University (to G. O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1–S4 and Figs. S1 and S2.

¹ To whom correspondence should be addressed: Dept. of Physical Chemistry-Biophysical Chemistry, Institute for Molecules and Materials, Radboud University, Toernooiveld 1, 6525 ED, Nijmegen, The Netherlands. E-mail: S.Wijmenga{at}nmr.ru.nl.

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