Human immunodeficiency virus type 1 Nef and p56lck protein-tyrosine kinase interact with a common element in CD4 cytoplasmic tail.
The human immunodeficiency virus type 1 nef gene induces endocytosis of CD4 antigen and disrupts the association between CD4 and p56lck protein-tyrosine kinase (EC 2.7.1.112). We demonstrate that in T cells these effects of the viral protein require a cluster of hydrophobic amino acids in a membrane-proximal region of the CD4 cytoplasmic tail; other amino acids in the C-terminal segment of CD4 cytoplasmic tail also contribute to the interaction. Mutations in CD4 that prevent down-modulation by Nef also decrease CD4 association with p56lck and prevent Nef-induced disruption of CD4-p56lck complexes. Together, the overlap in CD4 sequences required for interaction with Nef and p56lck and the tight correlation between Nef-induced CD4 down-modulation and disruption of CD4-p56lck association suggest that Nef, or cellular factors recruited by Nef, interact with this segment of CD4 to displace p56lck from the complex and induce CD4 endocytosis.
Salghetti
S
S
Cold Spring Harbor Laboratory, NY 11724.
Mariani
R
R
Skowronski
J
J
D000595:Amino Acid Sequence; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D004705:Endocytosis; D005786:Gene Expression Regulation; D015693:Gene Products, nef / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D054311:nef Gene Products, Human Immunodeficiency Virus
D015704:CD4 Antigens; D015693:Gene Products, nef; D009856:Oncogene Proteins, Viral; D054311:nef Gene Products, Human Immunodeficiency Virus; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D013755:Tetradecanoylphorbol Acetate