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J. Biol. Chem., Vol. 278, Issue 1, 372-381, January 3, 2003
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From the 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.
HIV-1 Integrase Forms Stable Tetramers and Associates with
LEDGF/p75 Protein in Human Cells*
§,
,,, and
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
*
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.
Aspirant of the Belgian National Fund for Scientific Research.
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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R. Lu, A. Limon, E. Devroe, P. A. Silver, P. Cherepanov, and A. Engelman Class II Integrase Mutants with Changes in Putative Nuclear Localization Signals Are Primarily Blocked at a Postnuclear Entry Step of Human Immunodeficiency Virus Type 1 Replication J. Virol., December 1, 2004; 78(23): 12735 - 12746. [Abstract] [Full Text] [PDF]
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P. Cherepanov, E. Devroe, P. A. Silver, and A. Engelman Identification of an Evolutionarily Conserved Domain in Human Lens Epithelium-derived Growth Factor/Transcriptional Co-activator p75 (LEDGF/p75) That Binds HIV-1 Integrase J. Biol. Chem., November 19, 2004; 279(47): 48883 - 48892. [Abstract] [Full Text] [PDF]
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M. Llano, M. Vanegas, O. Fregoso, D. Saenz, S. Chung, M. Peretz, and E. M. Poeschla LEDGF/p75 Determines Cellular Trafficking of Diverse Lentiviral but Not Murine Oncoretroviral Integrase Proteins and Is a Component of Functional Lentiviral Preintegration Complexes J. Virol., September 1, 2004; 78(17): 9524 - 9537. [Abstract] [Full Text] [PDF]
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 C. Marchand, A. A. Johnson, R. G. Karki, G. C. G. Pais, X. Zhang, K. Cowansage, T. A. Patel, M. C. Nicklaus, T. R. Burke Jr., and Y. Pommier Metal-Dependent Inhibition of HIV-1 Integrase by {beta}-Diketo Acids and Resistance of the Soluble Double-Mutant (F185K/C280S) Mol. Pharmacol., September 1, 2003; 64(3): 600 - 609. [Abstract] [Full Text] [PDF]
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G. Maertens, P. Cherepanov, W. Pluymers, K. Busschots, E. De Clercq, Z. Debyser, and Y. Engelborghs LEDGF/p75 Is Essential for Nuclear and Chromosomal Targeting of HIV-1 Integrase in Human Cells J. Biol. Chem., August 29, 2003; 278(35): 33528 - 33539. [Abstract] [Full Text] [PDF]
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S. Sandmeyer Integration by design PNAS, May 13, 2003; 100(10): 5586 - 5588. [Full Text] [PDF]
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