1H-13C nuclear magnetic resonance assignment and structural characterization of HIV-1 Tat protein

Péloponèse, Jean-Marie; Grégoire, Catherine; Opi, Sandrine; Esquieu, Didier; Sturgis, James N.; Lebrun, Évelyne; Meurs, Éliane; Collette, Yves; Olive, Daniel; Aubertin, Anne-Marie; Witvrow, Myriam; Pannecouque, Christophe; Clercq, Erik De; Bailly, Christian; Lebreton, Jacques; Loret, Erwann

doi:10.1016/s0764-4469(00)01228-2

Cited by 69 publications

(101 citation statements)

References 26 publications

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“…Furthermore, the sequence used for this study does not correspond to a viable HIV-1 strain, as the peptide contained a supplemental 20 residues at the N terminus that are unrelated to Tat (1). This study was in contradiction with three former twodimensional NMR studies that we published with Tat variants having the transactivation activity in a cellular assay and showing a conserved folding among Tat variants (11)(12)(13). However, structural heterogeneities in Tat variants are observed, which are localized mainly in region V, which can adopt an ␣ helix or a ␤ turn conformation as a function of mutations (1).…”

Section: Discussioncontrasting

confidence: 84%

“…Tat is divided into six different regions: region I (residues 1-21) is a proline-rich region and has a conserved Trp 11 ; region II (residues 22-37) has seven well conserved cysteines; region III (residues 38 -48) has a conserved Phe 38 and the conserved sequence 43 LGISYG; region IV (residues 49 -59) is rich in basic residues and has the rather well conserved sequence 49 RKKRRQRRRPP; region V (residues 60 -72) is the glutaminerich region and has the highest rate of sequence variation; and region VI constitutes the C terminus of Tat (1). The basic region (IV) appear to be the most important functional region of Tat because it is essential to cross the cell membrane and to bind on the trans-activating region an hairpin structure at the 5Ј-end of the viral mRNA, but it is not recognized by sera from HIV-1-infected patients due to sequence homology with human proteins such as protamine (1).…”

mentioning

confidence: 99%

“…There is a controversy regarding Tat structure with studies showing that Tat has a folding (10 -14) and studies showing that Tat is a naturally unfolded protein (15)(16). Tat NMR studies on full size Tat variants with the biological activity show that Trp 11 and Phe 38 constitute an hydrophobic core with other aliphatic residues from other regions, whereas most of regions II, III, IV, and VI are exposed to the solvent with ␤ turns constituting the main secondary structure (1). In the blood of HIV-1-infected patients, Tat variants are naturally folded proteins (17).…”

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confidence: 99%

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Identification of a Highly Conserved Surface on Tat Variants

Mediouni¹,

Darque²,

Ravaux³

et al. 2013

Journal of Biological Chemistry

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Background:The Tat OYI vaccine might reduce HIV-1-infected cells due to neutralizing antibodies targeting extracellular Tat. Results: MIMOOX is a peptide designed to mimic a three-dimensional epitope of Tat OYI-inducing neutralizing antibodies against Tat variants. Conclusion: There is a highly conserved surface on Tat variants that the Tat OYI vaccine helps to recognize. Significance: The Tat OYI vaccine could be an alternative to antiretroviral therapy.

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Section: Discussioncontrasting

confidence: 84%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Identification of a Highly Conserved Surface on Tat Variants

Mediouni¹,

Darque²,

Ravaux³

et al. 2013

Journal of Biological Chemistry

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“…Tat is nevertheless stabilized by interactions between the acidic N-terminal domain and the basic domain of the protein (39). A different conformation was observed at acidic pH (pH 4.1-4.5) using a similar 86-residue Tat (43). Regardless of whether these conformations are stable, transient, or molten globule-like, it seems that Trp-11 is poorly accessible to the solvent at mildly acidic pH (31) but is much more exposed to the outside at low pH (43).…”

Section: Discussionmentioning

confidence: 97%

Mechanism for HIV-1 Tat Insertion into the Endosome Membrane

Yezid¹,

Konate²,

Debaisieux³

et al. 2009

Journal of Biological Chemistry

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The human immunodeficiency virus, type 1, transactivating protein Tat is a small protein that is strictly required for viral transcription and multiplication within infected cells. The infected cells actively secrete Tat using an unconventional secretion pathway. Extracellular Tat can affect different cell types and induce severe cell dysfunctions ranging from cell activation to cell death. To elicit most cell responses, Tat needs to reach the cell cytosol. To this end, Tat is endocytosed, and low endosomal pH will then trigger Tat translocation to the cytosol. Although this translocation step is critical for Tat cytosolic delivery, how Tat could interact with the endosome membrane is unknown, and the key residues involved in this interaction require identification. We found that, upon acidification below pH 6.0 (i.e. within the endosomal pH range), Tat inserts into model membranes such as monolayers or lipid vesicles. This insertion process relies on Tat single Trp, Trp-11, which is not needed for transactivation and could be replaced by another aromatic residue for membrane insertion. Nevertheless, Trp-11 is strictly required for translocation. Tat conformational changes induced by low pH involve a sensor made of its first acidic residue (Glu/Asp-2) and the end of its basic domain (residues 55-57). Mutation of one of these elements results in membrane insertion above pH 6.5. Tat basic domain is also required for efficient Tat endocytosis and membrane insertion. Together with the strict conservation of Tat Trp among different virus isolates, our results point to an important role for Tat-membrane interaction in the multiplication of human immunodeficiency virus type 1.

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“…Both sequences come from patients with abnormal disease progression. Previous data have shown a correlation between progression rates and Tat activity (21). Ug05RP came from a patient that showed rapid progression, and Ug11LTS came from a patient described as an LTS.…”

Section: Tat From An Rp Patient Has a Superior Trans-activational Potmentioning

confidence: 99%