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Originally published In Press as doi:10.1074/jbc.M105421200 on November 21, 2001

J. Biol. Chem., Vol. 277, Issue 6, 4334-4342, February 8, 2002
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Functional Analyses of Human Apolipoprotein CII by Site-directed Mutagenesis
IDENTIFICATION OF RESIDUES IMPORTANT FOR ACTIVATION OF LIPOPROTEIN LIPASE*

Yan ShenDagger §, Aivar LookeneDagger , Solveig NilssonDagger , and Gunilla OlivecronaDagger ||

From the Dagger  Department of Medical Biosciences, Umeå University, Umeå SE-90 187, Sweden and  National Institute of Chemical Physics and Biophysics, Tallinn, Estonia

Apolipoprotein CII (apoCII) activates lipoprotein lipase (LPL). Seven residues, located on one face of a model alpha -helix spanning residues 59-75, are fully conserved in apoCII from ten different animal species. We have mutated these residues one by one. Substitution of Ala59 by glycine, or Thr62 and Gly65 by alanine did not change the activation, indicating that these residues are outside the LPL-binding site. Replacement of Tyr63, Ile66, Asp69, or Gln70 by alanine lowered the affinity for LPL and the catalytic activity of the LPL·apoCII complex. For each residue several additional replacements were made. Most mutants retained some activating ability, but replacement of Tyr63 by phenylalanine or tryptophan and Gln70 by glutamate caused almost complete loss of activity. All mutants bound to liposomes with similar affinity as wild-type apoCII, and they also bound with similar affinity to LPL in the absence of hydrolyzable lipids. However, the inactive mutants did not compete with wild-type apoCII in the activation assay. Therefore, we conclude that the productive apoCII·LPL interaction may be dependent on substrate molecules. In summary, our data demonstrate that residues 63, 66, 69, and 70 are of special importance for the function of apoCII, but no single amino acid residue is absolutely crucial.


* This work was supported by the Swedish Medical Research Council (Grants 727 and 12203), by the Swedish Royal Academy of Sciences, by the Estonian Science Foundation (Grant 4925), and by Donation Funds at the Medical Faculty, Umeå University.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Present address: Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129-2060.

|| To whom correspondence should be addressed. Tel.: 46-90-786-7762; Fax: 46-90-786-7840; E-mail: Gunilla.Olivecrona@medchem.umu.se.


Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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