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Structural basis for HIV-1 DNA integration in the human genome
Retrovirology volume 6, Article number: P79 (2009)
Integration of the human immunodeficiency virus type 1 (HIV-1) cDNA into the human genome is catalyzed by the viral integrase protein that requires the lens epithelium-derived growth factor (LEDGF), a cellular transcriptional coactivator. In the presence of LEDGF, integrase forms a stable complex in vitro and importantly becomes soluble by contrast with integrase alone which aggregates and precipitates. Using cryo-electron microscopy (EM) and single-particle reconstruction, we obtained three-dimensional structures of the wild type full length integrase-LEDGF complex with and without DNA . The stoichiometry of the complex was found to be (integrase)4-(LEDGF)2 by mass spectrometry analysis and existing atomic structures were unambiguous positioned in the EM map. In vitro functional assays reveal that LEDGF increases integrase activity likely in maintaining a stable and functional integrase structure. DNA-Protein cross-linking experiments show specific interaction between viral DNA and the C-terminal domain of integrase. Upon DNA binding, IN undergoes large conformational changes. Cryo-EM structure underlines the path of viral and target DNA and a model for DNA integration in human DNA is proposed (see fig. 1, overleaf).
Michel F, Crucifix C, Granger F, Eiler S, Mouscadet JF, Korolev S, Agapkina J, Ziganshin R, Gottikh M, Nazabal A, Emiliani S, Benarous R, Moras D, Schultz P, Ruff M: Structural basis for HIV-1 DNA integration in the human genome, role of the LEDGF/P75 cofactor. EMBO J. 2009, 28: 980-991. 10.1038/emboj.2009.41.
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Michel, F., Eiler, S., Granger, F. et al. Structural basis for HIV-1 DNA integration in the human genome. Retrovirology 6, P79 (2009) doi:10.1186/1742-4690-6-S2-P79
- Human Immunodeficiency Virus
- Mass Spectrometry Analysis
- Transcriptional Coactivator
- Large Conformational Change
- Integrase Protein