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Originally published In Press as doi:10.1074/jbc.M209278200 on October 28, 2002

J. Biol. Chem., Vol. 278, Issue 1, 372-381, January 3, 2003
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HIV-1 Integrase Forms Stable Tetramers and Associates with LEDGF/p75 Protein in Human Cells*

Peter CherepanovDagger §, Goedele Maertens||, Paul ProostDagger , Bart Devreese**, Jozef Van Beeumen**, Yves Engelborghs, Erik De ClercqDagger , and Zeger DebyserDagger Dagger Dagger

From the Dagger  Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000, Leuven, Belgium, the  Laboratory of Biomolecular Dynamics, Katholieke Universiteit Leuven, B-3001, Heverlee, Belgium, and the ** Laboratory for Protein Biochemistry & Protein Engineering, Ghent University, K. L. Ledeganckstraat 35, B-9000 Ghent, Belgium

We studied human immunodeficiency virus, type 1 (HIV-1) integrase (IN) complexes derived from nuclei of human cells stably expressing the viral protein from a synthetic gene. We show that in the nuclear extracts IN exists as part of a large distinct complex with an apparent Stokes radius of 61 Å, which dissociates upon dilution yielding a core molecule of 41 Å. We isolated the IN complexes from cells expressing FLAG-tagged IN and demonstrated that the 41 Å core is a tetramer of IN, whereas 61 Å molecules are composed of IN tetramers associated with a cellular protein with an apparent molecular mass of 76 kDa. This novel integrase interacting protein was found to be identical to lens epithelium-derived growth factor (LEDGF/p75), a protein implicated in regulation of gene expression and cellular stress response. HIV-1 IN and LEDGF co-localized in the nuclei of human cells stably expressing IN. Furthermore, recombinant LEDGF robustly enhanced strand transfer activity of HIV-1 IN in vitro. Our findings indicate that the minimal IN molecule in human cells is a homotetramer, suggesting that at least an octamer of IN is required to accomplish coordinated integration of both retroviral long terminal repeats and that LEDGF is a cellular factor involved in this process.

* This work was supported in part by the Concerted Research Action Fund of the Flemish Government.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.

§ To whom correspondence may be addressed. Tel.: 32-16-332176; Fax: 32-16-337340; E-mail: Peter.Cherepanov@uz.kuleuven.ac.be.

|| Aspirant of the Belgian National Fund for Scientific Research.

Dagger Dagger Postdoctoral Fellow of the Belgian National Fund for Scientific Research (F.W.O. Flanders). To whom correspondence may be addressed. Tel.: 32-16-332176; Fax: 32-16-337340; E-mail: Zeger. Debyser{at}uz.kuleuven.ac.be.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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