Simian Immunodeficiency Virus and Human Immunodeficiency Virus Type 1 Nef Proteins Show Distinct Patterns and Mechanisms of Src Kinase Activation

• DOI: 10.1128/jvi.73.7.6152-6158.1999
• Publication Date: 2019-12-31T18:35:28Z
• Authors: Alison L. Greenway; Hélène Dutartre; Kelly Allen; Dale A. McPhee; Daniel Olive; Yves Collette
• Keywords: 0303 health sciences; Recombinant Fusion Proteins; Molecular Sequence Data; Phosphotransferases; Protein-Tyrosine Kinases; Catalysis; Gene Products, nef; 3. Good health; Enzyme Activation; src Homology Domains; Jurkat Cells; 03 medical and health sciences; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); Proto-Oncogene Proteins; [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology; HIV-1; Proto-Oncogene Proteins c-hck; Animals; Humans; Simian Immunodeficiency Virus; Amino Acid Sequence; nef Gene Products, Human Immunodeficiency Virus

ABSTRACTThenefgene from human and simian immunodeficiency viruses (HIV and SIV) regulates cell function and viral replication, possibly through binding of thenefproduct to cellular proteins, including Src family tyrosine kinases. We show here that the Nef protein encoded by SIVmac239 interacts with and also activates the human Src kinases Lck and Hck. This is in direct contrast to the inhibitory effect of HIV type 1 (HIV-1) Nef on Lck catalytic activity. Unexpectedly, however, the interaction of SIV Nef with human Lck or Hck is not mediated via its consensus proline motif, which is known to mediate HIV-1 Nef binding to Src homology 3 (SH3) domains, and various experimental analyses failed to show significant interaction of SIV Nef with the SH3 domain of either kinase. Instead, SIV Nef can bind Lck and Hck SH2 domains, and its N-terminal 50 amino acid residues are sufficient for Src kinase binding and activation. Our results provide evidence for multiple mechanisms by which Nef binds to and regulates Src kinases.