The N-terminal structure of HIV-1 Tat is required for suppression of CD26-dependent T cell growth.
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.
Wrenger
S
S
Center for Internal Medicine, Institute of Experimental Internal Medicine, Otto-von-Guericke-University Magdeburg, D-39120 Magdeburg, Germany. dirk.reinhold@medizin.uni-magdeburg.de
Hoffmann
T
T
Faust
J
J
Mrestani-Klaus
C
C
Brandt
W
W
Neubert
K
K
Kraft
M
M
Olek
S
S
Frank
R
R
Ansorge
S
S
Reinhold
D
D
D019943:Amino Acid Substitution; D001665:Binding Sites; D001667:Binding, Competitive; D002455:Cell Division; D002478:Cells, Cultured; D018819:Dipeptidyl Peptidase 4 / Q000502:physiology*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors; D015696:Gene Products, tat / Q000737:chemistry*; D015497:HIV-1 / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology*; D013816:Thermodynamics; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D054322:tat Gene Products, Human Immunodeficiency Virus; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D018819:Dipeptidyl Peptidase 4