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If a protein meets these conditions... i

Common conditions

Special conditions

    • Subsequence at position 2 - 2 aligns to "G" in entry P04601 (individually applies "N-myristoyl glycine; by host")
    • Subsequence at position 6 - 6 aligns to "S" in entry P04601 (individually applies "Phosphoserine; by host")
    • Subsequence at position 20 - 20 aligns to "M" in entry P04601 (individually applies "Might play a role in AP-1 recruitment to the Nef-MHC-I complex")
    • Subsequence at position 57 - 58 aligns to "[FW]-L" in entry P04601 (individually applies "Cleavage; by viral protease")
    • Subsequence at position 62 - 65 aligns to entry P04601 (individually applies "Acidic; interacts with host PACS1 and PACS2; stabilizes the interaction of NEF/MHC-I with host AP1M1; necessary for MHC-I internalization")
    • Subsequence at position 69 - 78 aligns to entry P04601 (individually applies "SH3-binding; interaction with Src family tyrosine kinases")
    • Subsequence at position 72 - 75 aligns to "P-x(2)-P" in entry P04601 (individually applies "PxxP; stabilizes the interaction of NEF/MHC-I with host AP1M1; necessary for MHC-I internalization")
    • Subsequence at position 108 - 124 aligns to entry P04601 (individually applies "Mediates dimerization, Nef-PTE1 interaction")
    • Subsequence at position 148 - 180 aligns to entry P04601 (individually applies "Binding to ATP6V1H")
    • Subsequence at position 164 - 165 aligns to "L-L" in entry P04601 (individually applies "Dileucine internalization motif; necessary for CD4 internalization")
    • Subsequence at position 174 - 175 aligns to "[ED]-D" in entry P04601 (individually applies "Diacidic; necessary for CD4 internalization")
    • Subsequence at position @NTER|+1@ - @NTER|+1@ aligns to "M" in entry P04601 (individually applies "Removed; by host")

... then these annotations are applied i

Protein namei

  • Recommended name:
    Protein Nef
    Alternative name(s):
    Negative factor
    Short name:
    F-protein
    3'ORF

Cleaved chain(s) or included domain(s)i

  • Cleaved chain:
    Recommended name:
    C-terminal core protein

Gene namei

  • Name:nef

Miscellaneousi

  • HIV-1 lineages are divided in three main groups, M (for Major), O (for Outlier), and N (for New, or Non-M, Non-O). The vast majority of strains found worldwide belong to the group M. Group O seems to be endemic to and largely confined to Cameroon and neighboring countries in West Central Africa, where these viruses represent a small minority of HIV-1 strains. The group N is represented by a limited number of isolates from Cameroonian persons. The group M is further subdivided in 9 clades or subtypes (A to D, F to H, J and K).

Inductioni

  • Expressed early in the viral replication cycle.

Post-translational modificationi

  • Myristoylated.
  • Phosphorylated on serine residues, probably by host PKCdelta and theta.
  • The virion-associated Nef proteins are cleaved by the viral protease to release the soluble C-terminal core protein. Nef is probably cleaved concomitantly with viral structural proteins on maturation of virus particles.

Functioni

  • Bypasses host T-cell signaling by inducing a transcriptional program nearly identical to that of anti-CD3 cell activation. Interaction with TCR-zeta chain up-regulates the Fas ligand (FasL). Increasing surface FasL molecules and decreasing surface MHC-I molecules on infected CD4+ cells send attacking cytotoxic CD8+ T-lymphocytes into apoptosis.
  • Extracellular Nef protein targets CD4+ T-lymphocytes for apoptosis by interacting with CXCR4 surface receptors.
  • Factor of infectivity and pathogenicity, required for optimal virus replication. Alters numerous pathways of T-lymphocytes function and down-regulates immunity surface molecules in order to evade host defense and increase viral infectivity. Alters the functionality of other immunity cells, like dendritic cells, monocytes/macrophages and NK cells.
  • In infected CD4+ T-lymphocytes, down-regulates the surface MHC-I, mature MHC-II, CD4, CD28, CCR5 and CXCR4 molecules. Mediates internalization and degradation of host CD4 through the interaction of with the cytoplasmic tail of CD4, the recruitment of AP-2 (clathrin adapter protein complex 2), internalization through clathrin coated pits, and subsequent transport to endosomes and lysosomes for degradation. Diverts host MHC-I molecules to the trans-Golgi network-associated endosomal compartments by an endocytic pathway to finally target them for degradation. MHC-I down-regulation may involve AP-1 (clathrin adapter protein complex 1) or possibly Src family kinase-ZAP70/Syk-PI3K cascade recruited by PACS2. In consequence infected cells are masked for immune recognition by cytotoxic T-lymphocytes. Decreasing the number of immune receptors also prevents reinfection by more HIV particles (superinfection). Down-regulates host SERINC3 and SERINC5 thereby excluding these proteins from the viral particles. Virion infectivity is drastically higher when SERINC3 or SERINC5 are excluded from the viral envelope, because these host antiviral proteins impare the membrane fusion event necessary for subsequent virion penetration.
  • Plays a role in optimizing the host cell environment for viral replication without causing cell death by apoptosis. Protects the infected cells from apoptosis in order to keep them alive until the next virus generation is ready to strike. Inhibits the Fas and TNFR-mediated death signals by blocking MAP3K5/ASK1. Decreases the half-life of TP53, protecting the infected cell against p53-mediated apoptosis. Inhibits the apoptotic signals regulated by the Bcl-2 family proteins through the formation of a Nef/PI3-kinase/PAK2 complex that leads to activation of PAK2 and induces phosphorylation of host BAD.

Subunit structurei

  • Monomer; cytosolic form. Homodimer; membrane bound form. Interacts with Nef associated p21-activated kinase (PAK2); this interaction activates PAK2. Associates with the Nef-MHC-I-AP1 complex; this complex is required for MHC-I internalization. Interacts (via C-terminus) with host PI3-kinase. Interacts with host PACS1; this interaction seems to be weak. Interacts with host PACS2. Interacts with host LCK and MAPK3; these interactions inhibit the kinase activity of the latters. Interacts with host ATP6V1H; this interaction may play a role in CD4 endocytosis. Associates with the CD4-Nef-AP2 complex; this complex is required for CD4 internalization. Interacts with host AP2 subunit alpha and AP2 subunit sigma2. Interacts with TCR-zeta chain; this interaction up-regulates the Fas ligand (FasL) surface expression. Interacts with host HCK, LYN, and SRC; these interactions activate the Src family kinases. Interacts with MAP3K5; this interaction inhibits the Fas and TNFR-mediated death signals. Interacts with beta-COP and PTE1. Interacts with human RACK1; this increases Nef phosphorylation by PKC. Interacts with TP53; this interaction decreases the half-life of TP53, protecting the infected cell against p53-mediated apoptosis.

Domaini

  • The N-terminal domain is composed of the N-myristoyl glycine and of a cluster of positively charged amino acids. It is required for inner plasma membrane targeting of Nef and virion incorporation, and thereby for infectivity. This domain is also involved in binding to TP53.
  • The SH3-binding domain constituted of PxxP motifs mediates binding to several Src family proteins thereby regulating their tyrosine kinase activity. The same motifs also mediates the association with MAPK3, PI3-kinase and TCR-zeta.
  • The acidic region binds to the sorting protein PACS-2, which targets Nef to the paranuclear region, enabling the PxxP motif to direct assembly of an SFK/ZAP-70/PI3K complex that accelerates endocytosis of cell-surface MHC-I.
  • The dileucine internalization motif and a diacidic motif seem to be required for binding to AP-2.

Sequence similaritiesi