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J. Biol. Chem., Vol. 278, Issue 31, 29344-29351, August 1, 2003

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Calreticulin Promotes Folding/Dimerization of Human Lipoprotein Lipase Expressed in Insect Cells (Sf21)^*

Liyan Zhang , Gengshu Wu , Christopher G. Tate , Aivar Lookene  ¶ || and Gunilla Olivecrona  **

From the Department of Medical Biosciences, Physiological Chemistry, Umeå University, SE-901 87 Umeå, Sweden, MRC Laboratory of Molecular Biology, Cambridge CB2 2QH, United Kingdom, and the ^¶Department of Gene Technology, Tallinn Technical University, Tallinn 19086, Estonia

Lipoprotein lipase (LPL) is a non-covalent, homodimeric, N-glycosylated enzyme important for metabolism of blood lipids. LPL is regulated by yet unknown post-translational events affecting the levels of active dimers. On co-expression of LPL with human molecular chaperones, we found that calreticulin had the most pronounced effects on LPL activity, but calnexin was also effective. Calreticulin caused a 9-fold increase in active LPL, amounting to about 50% of the expressed LPL protein. The total expression of LPL protein was increased less than 20%, and the secretion rates for active and inactive LPL were not significantly changed by the chaperone. Thus, the main effect was an increased specific activity of LPL both in cells and media. Chromatography on heparin-Sepharose and sucrose density gradient centrifugation demonstrated that most of the inactive LPL was monomeric and that calreticulin promoted formation of active dimers. Higher oligomers of inactive LPL were present in cell extracts, but only monomers and dimers were secreted to the medium. Interaction between LPL and calreticulin was demonstrated, and the effect of the chaperone was prevented by castanospermine, an inhibitor of N-glycan glucose trimming. Our data indicate an important role of endoplasmic reticulum-based chaperones for the folding/dimerization of LPL.

Received for publication, January 15, 2003 , and in revised form, April 10, 2003.

^* This work was supported in part by the Swedish Medical Research Council Grant 31X-122030 and from the Biotechnology Fund at Umeå University. 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.

^|| Recipient of a scholarship from the Swedish Royal Academy of Sciences.

^** To whom correspondence should be addressed: Dept. of Medical Biosciences, Physiological Chemistry, Umeå University, Bldg. 6M, 3rd floor, SE-901 87 Umeå, Sweden. Tel.: 46-90-7854490; Fax: 46-90-785 4496; E-mail: Gunilla.Olivecrona{at}medbio.umu.se.

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