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      HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells.

      The Journal of Biological Chemistry
      Amino Acid Sequence, Cell Fractionation, Cell Line, Cell Nucleus, metabolism, Cross-Linking Reagents, HIV Integrase, chemistry, genetics, Humans, Intercellular Signaling Peptides and Proteins, Macromolecular Substances, Molecular Sequence Data, Molecular Weight, Peptides, Protein Structure, Quaternary, Recombinant Proteins, Succinimides, Virus Integration, physiology

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          Abstract

          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 A, which dissociates upon dilution yielding a core molecule of 41 A. We isolated the IN complexes from cells expressing FLAG-tagged IN and demonstrated that the 41 A core is a tetramer of IN, whereas 61 A 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.

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