NMR structure of the (1-51) N-terminal domain of the HIV-1 regulatory protein Vpr.
The human immunodeficiency virus type 1 (HIV-1) genome encodes a highly conserved 16 kDa regulatory gene product, Vpr (viral protein of regulation, 96 amino acid residues), which is incorporated into virions, in quantities equivalent to those of the viral Gag proteins. In the infected cells, Vpr is believed to function in the early phase of HIV-1 replication, including nuclear migration of preintegration complex, transcription of the provirus genome and viral multiplication by blocking cells in the G2 phase. Vpr has a critical role in long-term AIDS disease by inducing infection in nondividing cells such as monocytes and macrophages. Mutations have suggested that the N-terminal domain of Vpr encompassing the first 40 residues could be required for nuclear localization, packaging into virions and binding of transcription factor (TFIIB, Sp1), viral proteins (p6) and cellular proteins (RIP1, UNG, karyopherins). To gain insight into the structure-function relationship of Vpr, (1-51)Vpr was synthesized and its structure analyzed by circular dichroism and two-dimensional 1H NMR in aqueous trifluoroethanol (30%) solution and refined by restrained molecular dynamics. The structure is characterized by three turns around the first three prolines, Pro5, Pro10, Pro14, followed by a long amphipathic alpha helix-turn-alpha helix (Asp17-Ile46) motif ended by a turn extending from Tyr47 to Thr49. The alpha helix-turn-alpha helix motif and the amphipathic helix are well known for being implicated in protein-protein or protein-nucleic acid interaction. Therefore structural characteristics of the (1-51) N-terminal fragment of Vpr could explain why this region of Vpr plays a role in several biological functions of this protein.
Wecker
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Département de Pharmacochemie Moléculair et Structurale, INSERM U266--CNRS UMR 8600, UFR des Sciences Pharmaceutiques et Biologiques, Paris, France.
Roques
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D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002467:Cell Nucleus / Q000378:metabolism; D002942:Circular Dichroism; D016336:Gene Products, vpr / Q000737:chemistry* / Q000235:genetics*; D006801:Humans; D050356:Lipid Metabolism; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010452:Peptide Biosynthesis; D010455:Peptides / Q000737:chemistry; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013696:Temperature
D016336:Gene Products, vpr; D010455:Peptides