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J. Biol. Chem., Vol. 279, Issue 48, 49964-49972, November 26, 2004

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Rapid Subunit Exchange in Dimeric Lipoprotein Lipase and Properties of the Inactive Monomer^*

Aivar Lookene, Liyan Zhang, Magnus Hultin¶, and Gunilla Olivecrona||

From the Department of Medical Biosciences, Physiological Chemistry, Umeå University, SE-901 87 Umeå, Sweden, Department of Gene Technology, Tallinn Technical University, Tallinn 12618, Estonia, and ^¶Department of Surgical and Perioperative Sciences, Umeå University, SE-901 85 Umeå, Sweden

Lipoprotein lipase (LPL), a key enzyme in the metabolism of triglyceride-rich plasma lipoproteins, is a homodimer. Dissociation to monomers leads to loss of activity. Evidence that LPL dimers rapidly exchange subunits was demonstrated by fluorescence resonance energy transfer between lipase subunits labeled with Oregon Green and tetrametylrhodamine, respectively, and also by formation of heterodimers composed of radiolabeled and biotinylated lipase subunits captured on streptavidine-agarose. Compartmental modeling of the inactivation kinetics confirmed that rapid subunit exchange must occur. Studies of activity loss indicated the existence of a monomer that can form catalytically active dimers, but this intermediate state has not been possible to isolate and remains hypothetical. Differences in solution properties and conformation between the stable but catalytically inactive monomeric form of LPL and the active dimers were studied by static light scattering, intrinsic fluorescence, and probing with 4,4'-dianilino-1,1'-binaphtyl-5,5'-disulfonic acid and acrylamide. The catalytically inactive monomer appeared to have a more flexible and exposed structure than the dimers and to be more prone to aggregation. By limited proteolysis the conformational changes accompanying dissociation of the dimers to inactive monomers were localized mainly to the central part of the subunit, probably corresponding to the region for subunit interaction.

Received for publication, July 2, 2004 , and in revised form, September 20, 2004.

^* This study was supported by Grant 12203 from the Swedish Research Council, Grant 4925 from the Estonian Science Foundation, and a scholarship from the Swedish Royal Academy of Sciences (to A. L.). 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.

^|| To whom correspondence should be addressed: Dept. of Medical Biosciences, Physiological Chemistry, Umeå University, Bldg. 6M, 3rd Fl., SE-901 87 Umeå, Sweden. Tel.: 46-90-7854491; Fax: 46-90-7854496; E-mail: Gunilla.Olivecrona{at}medbio.umu.se.

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