Interaction between the HIV-1 protein Vpr and the adenine nucleotide translocator.
The HIV-1 protein Vpr circulates in the serum of seropositive individuals and in the cerebrospinal fluid of AIDS patients with neurological disorders. Vpr triggers apoptosis of numerous cell types after extracellular addition, vpr gene transfer or in the context of viral infection. Moreover, in vivo, transgenic mice over-expressing Vpr have enhanced T lymphocytes apoptosis. In previous studies, we suggested that the Vpr apoptotic activities were because of its binding to the adenine nucleotide translocator (ANT), a mitochondrial ATP/ADP antiporter. To specify this interaction, fragments of both proteins were synthesized and used in biochemical and biophysical experiments. We demonstrate here that in vitro, the (27-51) and (71-82) Vpr peptides bind to a region encompassing the first ANT intermembrane space loop and part of its second and third transmembrane helices. Computational analysis using a docking program associated to dynamic simulations enabled us to construct a three-dimensional model of the Vpr-ANT complex. In this model, the N-terminus of Vpr plunges in the ANT cavity whereas the Vpr C-terminal extremity is located at the surface of the ANT allowing possible interactions with a third partner. These results could be used to design molecules acting as pro-apoptotic Vpr analogs or as apoptosis inhibitors preventing the Vpr-ANT interaction.
Unité de Pharmacochimie Moléculaire et Structurale, INSERM U266, CNRS UMR 8600, Université René Descartes, UFR des Sciences Pharmaceutiques et Biologiques, 75270 Paris Cedex 06, France.
Emmanuelle N
EN
Sabbah
S
S
Druillennec
N
N
Morellet
S
S
Bouaziz
G
G
Kroemer
B P
BP
Roques
D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000627:therapeutic use; D017209:Apoptosis; D015195:Drug Design; D016336:Gene Products, vpr / Q000097:blood / Q000134:cerebrospinal fluid / Q000737:chemistry*; D006679:HIV Seropositivity / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D000226:Mitochondrial ADP, ATP Translocases / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020349:Surface Plasmon Resonance / Q000379:methods; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology; D054325:vpr Gene Products, Human Immunodeficiency Virus
D019380:Anti-HIV Agents; D016336:Gene Products, vpr; D054325:vpr Gene Products, Human Immunodeficiency Virus; D000226:Mitochondrial ADP, ATP Translocases