Omanische Heilpflanze im Fokus der Phytochemie IPB-Wissenschaftler und Partner aus Dhofar haben jüngst die omanische Heilpflanze Terminalia dhofarica unter die phytochemische Lupe genommen. Die Pflanze ist reich an…
Geschmack ist vorhersagbar: Mit FlavorMiner. FlavorMiner heißt das Tool, das IPB-Chemiker und Partner aus Kolumbien jüngst entwickelt haben. Das Programm kann, basierend auf maschinellem Lernen (KI), anhand der…
Wrenger, S.; Faust, J.; Mrestani-Klaus, C.; Fengler, A.; Stöckel-Maschek, A.; Lorey, S.; Kähne, T.; Brandt, W.; Neubert, K.; Ansorge, S.; Reinhold, D.;Down-regulation of T Cell Activation following Inhibition of Dipeptidyl Peptidase IV/CD26 by the N-terminal Part of the Thromboxane A2 ReceptorJ. Biol. Chem.27522180-22186(2000)DOI: 10.1074/jbc.M002338200
Using synthetic inhibitors, it has been shown that the ectopeptidase dipeptidyl peptidase IV (DP IV) (CD26) plays an important role in the activation and proliferation of T lymphocytes. The human immunodeficiency virus-1 Tat protein, as well as the N-terminal nonapeptide Tat(1–9) and other peptides containing the N-terminal sequence XXP, also inhibit DP IV and therefore T cell activation. Studying the effect of amino acid exchanges in the N-terminal three positions of the Tat(1–9) sequence, we found that tryptophan in position 2 strongly improves DP IV inhibition. NMR spectroscopy and molecular modeling show that the effect of Trp2-Tat(1–9) could not be explained by significant alterations in the backbone structure and suggest that tryptophan enters favorable interactions with DP IV. Data base searches revealed the thromboxane A2 receptor (TXA2-R) as a membrane protein extracellularly exposing N-terminal MWP. TXA2-R is expressed within the immune system on antigen-presenting cells, namely monocytes. The N-terminal nonapeptide of TXA2-R, TXA2-R(1–9), inhibits DP IV and DNA synthesis and IL-2 production of tetanus toxoid-stimulated peripheral blood mononuclear cells. Moreover, TXA2-R(1–9) induces the production of the immunosuppressive cytokine transforming growth factor-β1. These data suggest that the N-terminal part of TXA2-R is an endogenous inhibitory ligand of DP IV and may modulate T cell activation via DP IV/CD26 inhibition.
Publikation
Wrenger, S.; Hoffmann, T.; Faust, J.; Mrestani-Klaus, C.; Brandt, W.; Neubert, K.; Kraft, M.; Olek, S.; Frank, R.; Ansorge, S.; Reinhold, D.;The N-terminal Structure of HIV-1 Tat Is Required for Suppression of CD26-dependent T Cell GrowthJ. Biol. Chem.27230283-30288(1997)DOI: 10.1074/jbc.272.48.30283
Evidence exists that the human immunodeficiency virus-1 (HIV-1) transactivator Tat occurs extracellularly and is involved in the immunosuppression of non-HIV-1-infected T cells of acquired immunodeficiency syndrome (AIDS) patients. The mechanism of this immunosuppressive activity of Tat has been controversially discussed. Interestingly, Tat binds to the T cell activation marker CD26, which has been shown to play a key role in the regulation of growth of lymphocytes and to inhibit its dipeptidyl peptidase IV (DP IV) activity. Here we show that the N-terminal nonapeptide MDPVDPNIE of Tat is a competitive inhibitor of DP IV and suppresses DNA synthesis of tetanus toxoid-stimulated peripheral blood mononuclear cells. Amino acid exchanges at positions 5 and 6 strongly weaken these effects.1H nuclear magnetic resonance and molecular dynamics simulations of Tat(1–9), I5-Tat(1–9), and L6-Tat(1–9) suggest a similar backbone conformation for Tat(1–9) and L6-Tat(1–9). The solution conformation of I5-Tat(1–9) considerably differs from the other two. However, Tat(1–9) fits into our previously proposed active site model of DP IV in contrast to I5-Tat(1–9) and L6-Tat(1–9). Conformational alterations with regard to the parent peptide and spatial hindrances between these both compounds and DP IV can explain the loss of inhibitory activity. Our data suggest that the N-terminal residues of HIV-1 Tat do interact directly with the active site of DP IV and that DP IV does mediate Tat’s immunosuppressive effects.