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Homonuclear (1)H-NMR assignment and structural characterization of human immunodeficiency virus type 1 Tat Mal protein.

Grégoire C, Péloponèse JM, Esquieu D, Opi S, Campbell G, Solomiac M, Lebrun E, Lebreton J, Loret EP
Biopolymers 62 324-35 (2001)
Cited: 38 times
EuropePMC logo PMID: 11857271

Abstract

The transacting transcriptional activator (Tat) is a viral protein essential for activation of the human immunodeficiency virus (HIV) genes, and it plays an important role in HIV induced immunodeficiency. We report the NMR structural characterization of the active Tat Mal variant that belongs to a highly virulent D-subtype HIV type-1 (HIV-1) strain (Mal) found mainly in Africa. A full Tat Mal protein (87 residues) is synthesized. This synthetic protein is active in a transactivation assay with HeLa cells infected with the HIV long terminal repeated noncoding sequences of the HIV-1 provirus (LTR) lac Z gene. Homonuclear (1)H-NMR spectra allows the sequential assignment of the Tat Mal spin systems. Simulating annealing generates 20 conformers with similar folding. The geometry of the mean structure is optimized with energy minimization to obtain a final structure. As the European variant (Tat Bru) the N-terminal region of Tat Mal constitutes the core, and there is a hydrophobic pocket composed of the conserved Trp 11 interacting with several aromatic residues. The two functional regions of Tat (basic and the cysteine-rich regions) are well exposed to the solvent. A short alpha-helix is observed in region V adjacent to the basic region. This alpha helix induces local structural variations compared to the NMR structure of Tat Bru, and it brings the cysteine-rich and basic regions closer. This study suggests that similar folding exists among Tat variants.

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  1. Role of Tat protein in HIV neuropathogenesis. Li W, Li G, Steiner J, Nath A. Neurotox Res 16 205-220 (2009)
  2. Membrane Active Peptides and Their Biophysical Characterization. Avci FG, Akbulut BS, Ozkirimli E. Biomolecules 8 E77 (2018)
  3. What does the structure-function relationship of the HIV-1 Tat protein teach us about developing an AIDS vaccine? Campbell GR, Loret EP. Retrovirology 6 50 (2009)
  4. Tits and bits of HIV Tat protein. Johri MK, Mishra R, Chhatbar C, Unni SK, Singh SK. Expert Opin Biol Ther 11 269-283 (2011)
  5. HIV-1 Tat-based vaccines: an overview and perspectives in the field of HIV/AIDS vaccine development. Caputo A, Gavioli R, Bellino S, Longo O, Tripiciano A, Francavilla V, Sgadari C, Paniccia G, Titti F, Cafaro A, Ferrantelli F, Monini P, Ensoli F, Ensoli B. Int Rev Immunol 28 285-334 (2009)
  6. Functional roles of HIV-1 Tat protein in the nucleus. Musinova YR, Sheval EV, Dib C, Germini D, Vassetzky YS. Cell Mol Life Sci 73 589-601 (2016)
  7. Fab'-induced folding of antigenic N-terminal peptides from intrinsically disordered HIV-1 Tat revealed by X-ray crystallography. Serrière J, Dugua JM, Bossus M, Verrier B, Haser R, Gouet P, Guillon C. J Mol Biol 405 33-42 (2011)
  8. HIV-1 Tat amino acid residues that influence Tat-TAR binding affinity: a scoping review. Gotora PT, van der Sluis R, Williams ME. BMC Infect Dis 23 164 (2023)

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