The glutamine-rich region of the HIV-1 Tat protein is involved in T-cell apoptosis.
Human immunodeficiency virus (HIV) infection and the progression to AIDS are characterized by the depletion of CD4(+) T-cells. HIV-1 infection leads to apoptosis of uninfected bystander cells and the direct killing of HIV-infected cells. This is mediated, in part, by the HIV-1 Tat protein, which is secreted by virally infected cells and taken up by uninfected cells. We chemically synthesized two 86-residue subtype D Tat proteins, Ug05RP and Ug11LTS, from two Ugandan patients who were clinically categorized as either rapid progressor or long-term survivor, with non-conservative mutations located essentially in the glutamine-rich region. Structural heterogeneities were revealed by CD, which translate into differing trans-activational and apoptotic effects. CD data analysis and molecular modeling indicated that the short alpha-helix observed in subtype D Tat proteins from rapid progressor patients such as Tat Mal and Tat Ug05RP is not present in Ug11LTS. We show that Tat Ug05RP is more efficient than Tat Ug11LTS in its trans-activational role and in inducing apoptosis in binding tubulin via the mitochondrial pathway. The glutamine-rich region of Tat appears to be involved in the Tat-mediated apoptosis of T-cells.
Campbell
Grant R
GR
CNRS Formation de Recherche en Evolution 2737, Faculté de Pharmacie, Université de la Méditerranée, 27, Boulevard Jean Moulin, 13385 Marseille, France.
Pasquier
Eddy
E
Watkins
Jennifer
J
Bourgarel-Rey
Veronique
V
Peyrot
Vincent
V
Esquieu
Didier
D
Barbier
Pascale
P
de Mareuil
Jean
J
Braguer
Diane
D
Kaleebu
Pontiano
P
Yirrell
David L
DL
Loret
Erwann P
EP
D000595:Amino Acid Sequence; D017209:Apoptosis / Q000502:physiology*; D002942:Circular Dichroism; D018450:Disease Progression; D053222:Fas Ligand Protein; D015696:Gene Products, tat / Q000138:chemical synthesis / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1 / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D015533:Transcriptional Activation; D014404:Tubulin / Q000378:metabolism; D014454:Uganda; D054322:tat Gene Products, Human Immunodeficiency Virus
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D015696:Gene Products, tat; D008562:Membrane Glycoproteins; D014404:Tubulin; D054322:tat Gene Products, Human Immunodeficiency Virus; D005973:Glutamine