Article
- The EMBO Journal (2009) 28, 980 - 991
- doi:10.1038/emboj.2009.41
Published online: 19 February 2009
Subject Categories:
Structural basis for HIV-1 DNA integration in the human genome, role of the LEDGF/P75 cofactor
Fabrice Michel1, Corinne Crucifix1, Florence Granger1, Sylvia Eiler1, Jean-François Mouscadet2, Sergei Korolev3, Julia Agapkina3, Rustam Ziganshin3, Marina Gottikh3, Alexis Nazabal4, Stéphane Emiliani5,6, Richard Benarous7, Dino Moras1, Patrick Schultz1 and Marc Ruff1
- IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Département de Biologie et de Génomique Structurales, UDS, CNRS, INSERM, Illkirch, France
- Laboratoire de Biotechnologie et Pharmacologie Génétique Appliquée, CNRS, ENS-Cachan, Institut d'Alembert, Cachan, France
- Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia
- Department of Chemistry and Applied Biosciences ETH Zurich and CovalX, Technoparkstrasse, Zürich, Switzerland
- Institut Cochin, Département des Maladies Infectieuses, Université Paris Descartes, CNRS, Paris, France
- Inserm, Paris, France
- CellVir, Evry, France
Correspondence to:
Patrick Schultz, Department of Structural Biology and Genomics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, Illkirch 67404, France. Tel.: +33 0388 6557 50; Fax: +33 0388 6532 76; E-mail: patrick.schultz@igbmc.fr
Marc Ruff, Department of Structural Biology and Genomics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, Illkirch 67404, France. Tel.: +33 0388 6533 50; Fax: +33 0388 6532 76; E-mail: marc.ruff@igbmc.fr
Received 17 December 2008; Accepted 26 January 2009
Abstract
Integration of the human immunodeficiency virus (HIV-1) cDNA into the human genome is catalysed by integrase. Several studies have shown the importance of the interaction of cellular cofactors with integrase for viral integration and infectivity. In this study, we produced a stable and functional complex between the wild-type full-length integrase (IN) and the cellular cofactor LEDGF/p75 that shows enhanced in vitro integration activity compared with the integrase alone. Mass spectrometry analysis and the fitting of known atomic structures in cryo negatively stain electron microscopy (EM) maps revealed that the functional unit comprises two asymmetric integrase dimers and two LEDGF/p75 molecules. In the presence of DNA, EM revealed the DNA-binding sites and indicated that, in each asymmetric dimer, one integrase molecule performs the catalytic reaction, whereas the other one positions the viral DNA in the active site of the opposite dimer. The positions of the target and viral DNAs for the 3' processing and integration reaction shed light on the integration mechanism, a process with wide implications for the understanding of viral-induced pathologies.
Keywords:
- cryo-electron microscopy,
- DNA integration,
- HIV-1,
- integrase,
- LEDGF–P75
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