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Papers In Press, published online ahead of print September 14, 2004
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115
Corresponding Author: alan_engelman{at}dfci.harvard.edu
Human lens epithelium-derived growth factor/transcriptional co-activator p75 (LEDGF/p75) protein was recently identified as a binding partner for HIV-1 integrase (IN) in human cells. In this work, we used biochemical and bioinformatic approaches to define the domain organization of LEDGF/p75. Using limited proteolysis and deletion mutagenesis we show that the protein contains a pair of evolutionarily-conserved domains, assuming about 35% of its sequence. While the amino-terminal PWWP domain had been recognized previously, the second domain is novel. It is comprised of approximately 80 amino acid residues and is both necessary and sufficient for binding to HIV-1 IN. Strikingly, the integrase-binding domain (IBD) is not unique to LEDGF/p75, as a second human protein, hepatoma-derived growth factor-related protein 2 (HRP2), contains a homologous sequence. LEDGF/p75 and HRP2 IBDs avidly bound HIV-1 IN in an in vitro GST pull-down assay and each full-length protein potently stimulated HIV-1 IN activity in vitro. LEDGF/p75 and HRP2 are predicted to share a similar domain organization and have an evident evolutionary and likely functional relationship.
J. Biol. Chem, 10.1074/jbc.M406307200
Submitted on June 7, 2004
Revised on August 24, 2004
Accepted on September 13, 2004
Identification of an evolutionarily-conserved domain in LEDGF/p75 that binds HIV-1 integrase
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