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.
Cold Spring Harbor Laboratory, NY 11724.
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Salghetti
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Mariani
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Skowronski
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