JVI Accepts, published online ahead of print on 4 November 2009

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J. Virol. doi:10.1128/JVI.01043-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Implication of Serine Residues 271, 273 and 275 in the HIV-1 Cofactor Activity of LEDGF/p75.

Jose A. Garcia-Rivera, Murilo T.D. Bueno, Elisa Morales, Jeffrey R. Kugelman, Daniel F. Rodriguez, and Manuel Llano^*

Department of Biological Sciences, University of Texas at El Paso, 500 West University Ave. El Paso, TX 79968 USA

^* To whom correspondence should be addressed. Email: mllano{at}utep.edu.

The lens epithelium-derived growth factor/p75 (LEDGF/p75) is a cellular cofactor for HIV-1 DNA integration. It is well established that simultaneous binding of LEDGF/p75 to chromatin and to HIV-1 integrase are required for its cofactor activity. However, the exact molecular mechanism of LEDGF/p75 in HIV-1 integration has not been completely understood yet. Our hypothesis is that evolutionarily conserved regions in LEDGF/p75, exposed to solvent and harboring post-translational modifications may be involved in its HIV-1 cofactor activity. Therefore, a panel of LEDGF/p75 deletion mutants targeting these protein regions was evaluated for their HIV-1 cofactor activity, chromatin binding, integrase interaction and integrase to chromatin tethering activity using different cellular and biochemical approaches. Deletion of amino acids 267-281 reduced the cofactor activity of LEDGF/p75 to levels observed in chromatin-binding defective mutants. This region contains a serine cluster (residues 271, 273 and 275) recurrently found to be phosphorylated in both human and mouse cells. Importantly, conversion of these Ser residues to Ala was sufficient to impair the ability of LEDGF/p75 to mediate HIV-1 DNA integration, although these mutations did not alter chromatin binding, integrase binding, or the integrase to chromatin tethering capability of LEDGF/p75. These results clearly indicated that serine residues 271, 273 and 275 influence the HIV-1 cofactor activity of an integrase to chromatin tethering competent LEDGF/p75.