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Database: UniProt
Entry: NEF_SIVEK
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ID   NEF_SIVEK               Reviewed;         206 AA.
AC   Q1A242;
DT   05-SEP-2006, integrated into UniProtKB/Swiss-Prot.
DT   23-JAN-2007, sequence version 3.
DT   11-DEC-2019, entry version 72.
DE   RecName: Full=Protein Nef {ECO:0000255|HAMAP-Rule:MF_04078};
DE   AltName: Full=3'ORF {ECO:0000255|HAMAP-Rule:MF_04078};
DE   AltName: Full=Negative factor {ECO:0000255|HAMAP-Rule:MF_04078};
DE            Short=F-protein {ECO:0000255|HAMAP-Rule:MF_04078};
DE   Contains:
DE     RecName: Full=C-terminal core protein {ECO:0000255|HAMAP-Rule:MF_04078};
GN   Name=nef {ECO:0000255|HAMAP-Rule:MF_04078};
OS   Simian immunodeficiency virus (isolate EK505) (SIV-cpz) (Chimpanzee
OS   immunodeficiency virus).
OC   Viruses; Ortervirales; Retroviridae; Orthoretrovirinae; Lentivirus.
OX   NCBI_TaxID=388912;
OH   NCBI_TaxID=9598; Pan troglodytes (Chimpanzee).
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX   PubMed=16728595; DOI=10.1126/science.1126531;
RA   Keele B.F., Van Heuverswyn F., Li Y., Bailes E., Takehisa J.,
RA   Santiago M.L., Bibollet-Ruche F., Chen Y., Wain L.V., Liegeois F., Loul S.,
RA   Ngole E.M., Bienvenue Y., Delaporte E., Brookfield J.F., Sharp P.M.,
RA   Shaw G.M., Peeters M., Hahn B.H.;
RT   "Chimpanzee reservoirs of pandemic and nonpandemic HIV-1.";
RL   Science 313:523-526(2006).
CC   -!- FUNCTION: Factor of infectivity and pathogenicity, required for optimal
CC       virus replication. Alters numerous pathways of T-lymphocytes function
CC       and down-regulates immunity surface molecules in order to evade host
CC       defense and increase viral infectivity. Alters the functionality of
CC       other immunity cells, like dendritic cells, monocytes/macrophages and
CC       NK cells. {ECO:0000255|HAMAP-Rule:MF_04078}.
CC   -!- FUNCTION: In infected CD4(+) T-lymphocytes, down-regulates the surface
CC       MHC-I, mature MHC-II, CD4, CD28, CCR5 and CXCR4 molecules. Mediates
CC       internalization and degradation of host CD4 through the interaction of
CC       with the cytoplasmic tail of CD4, the recruitment of AP-2 (clathrin
CC       adapter protein complex 2), internalization through clathrin coated
CC       pits, and subsequent transport to endosomes and lysosomes for
CC       degradation. Diverts host MHC-I molecules to the trans-Golgi network-
CC       associated endosomal compartments by an endocytic pathway to finally
CC       target them for degradation. MHC-I down-regulation may involve AP-1
CC       (clathrin adapter protein complex 1) or possibly Src family kinase-
CC       ZAP70/Syk-PI3K cascade recruited by PACS2. In consequence infected
CC       cells are masked for immune recognition by cytotoxic T-lymphocytes.
CC       Decreasing the number of immune receptors also prevents reinfection by
CC       more HIV particles (superinfection). Down-regulates host SERINC3 and
CC       SERINC5 thereby excluding these proteins from the viral particles.
CC       Virion infectivity is drastically higher when SERINC3 or SERINC5 are
CC       excluded from the viral envelope, because these host antiviral proteins
CC       impare the membrane fusion event necessary for subsequent virion
CC       penetration. {ECO:0000255|HAMAP-Rule:MF_04078}.
CC   -!- FUNCTION: Bypasses host T-cell signaling by inducing a transcriptional
CC       program nearly identical to that of anti-CD3 cell activation.
CC       Interaction with TCR-zeta chain up-regulates the Fas ligand (FasL).
CC       Increasing surface FasL molecules and decreasing surface MHC-I
CC       molecules on infected CD4(+) cells send attacking cytotoxic CD8+ T-
CC       lymphocytes into apoptosis. {ECO:0000255|HAMAP-Rule:MF_04078}.
CC   -!- FUNCTION: Plays a role in optimizing the host cell environment for
CC       viral replication without causing cell death by apoptosis. Protects the
CC       infected cells from apoptosis in order to keep them alive until the
CC       next virus generation is ready to strike. Inhibits the Fas and TNFR-
CC       mediated death signals by blocking MAP3K5/ASK1. Decreases the half-life
CC       of TP53, protecting the infected cell against p53-mediated apoptosis.
CC       Inhibits the apoptotic signals regulated by the Bcl-2 family proteins
CC       through the formation of a Nef/PI3-kinase/PAK2 complex that leads to
CC       activation of PAK2 and induces phosphorylation of host BAD.
CC       {ECO:0000255|HAMAP-Rule:MF_04078}.
CC   -!- FUNCTION: Extracellular Nef protein targets CD4(+) T-lymphocytes for
CC       apoptosis by interacting with CXCR4 surface receptors.
CC       {ECO:0000255|HAMAP-Rule:MF_04078}.
CC   -!- SUBUNIT: Monomer; cytosolic form. Homodimer; membrane bound form.
CC       Interacts with Nef associated p21-activated kinase (PAK2); this
CC       interaction activates PAK2. Associates with the Nef-MHC-I-AP1 complex;
CC       this complex is required for MHC-I internalization. Interacts (via C-
CC       terminus) with host PI3-kinase. Interacts with host PACS1; this
CC       interaction seems to be weak. Interacts with host PACS2. Interacts with
CC       host LCK and MAPK3; these interactions inhibit the kinase activity of
CC       the latters. Interacts with host ATP6V1H; this interaction may play a
CC       role in CD4 endocytosis. Associates with the CD4-Nef-AP2 complex; this
CC       complex is required for CD4 internalization. Interacts with host AP2
CC       subunit alpha and AP2 subunit sigma2. Interacts with TCR-zeta chain;
CC       this interaction up-regulates the Fas ligand (FasL) surface expression.
CC       Interacts with host HCK, LYN, and SRC; these interactions activate the
CC       Src family kinases. Interacts with MAP3K5; this interaction inhibits
CC       the Fas and TNFR-mediated death signals. Interacts with beta-COP and
CC       PTE1. Interacts with human RACK1; this increases Nef phosphorylation by
CC       PKC. Interacts with TP53; this interaction decreases the half-life of
CC       TP53, protecting the infected cell against p53-mediated apoptosis.
CC       {ECO:0000255|HAMAP-Rule:MF_04078}.
CC   -!- SUBCELLULAR LOCATION: Host cell membrane {ECO:0000255|HAMAP-
CC       Rule:MF_04078}; Lipid-anchor {ECO:0000255|HAMAP-Rule:MF_04078};
CC       Cytoplasmic side {ECO:0000255|HAMAP-Rule:MF_04078}. Virion
CC       {ECO:0000255|HAMAP-Rule:MF_04078}. Secreted {ECO:0000255|HAMAP-
CC       Rule:MF_04078}. Host Golgi apparatus membrane {ECO:0000255|HAMAP-
CC       Rule:MF_04078}. Note=TGN localization requires PACS1. Associates with
CC       the inner plasma membrane through its N-terminal domain. Nef stimulates
CC       its own export via the release of exosomes. Incorporated in virions at
CC       a rate of about 10 molecules per virion, where it is cleaved.
CC       {ECO:0000255|HAMAP-Rule:MF_04078}.
CC   -!- INDUCTION: Expressed early in the viral replication cycle.
CC       {ECO:0000255|HAMAP-Rule:MF_04078}.
CC   -!- DOMAIN: The N-terminal domain is composed of the N-myristoyl glycine
CC       and of a cluster of positively charged amino acids. It is required for
CC       inner plasma membrane targeting of Nef and virion incorporation, and
CC       thereby for infectivity. This domain is also involved in binding to
CC       TP53. {ECO:0000255|HAMAP-Rule:MF_04078}.
CC   -!- DOMAIN: The SH3-binding domain constituted of PxxP motifs mediates
CC       binding to several Src family proteins thereby regulating their
CC       tyrosine kinase activity. The same motifs also mediates the association
CC       with MAPK3, PI3-kinase and TCR-zeta. {ECO:0000255|HAMAP-Rule:MF_04078}.
CC   -!- DOMAIN: The dileucine internalization motif and a diacidic motif seem
CC       to be required for binding to AP-2. {ECO:0000255|HAMAP-Rule:MF_04078}.
CC   -!- DOMAIN: The acidic region binds to the sorting protein PACS-2, which
CC       targets Nef to the paranuclear region, enabling the PxxP motif to
CC       direct assembly of an SFK/ZAP-70/PI3K complex that accelerates
CC       endocytosis of cell-surface MHC-I. {ECO:0000255|HAMAP-Rule:MF_04078}.
CC   -!- PTM: The virion-associated Nef proteins are cleaved by the viral
CC       protease to release the soluble C-terminal core protein. Nef is
CC       probably cleaved concomitantly with viral structural proteins on
CC       maturation of virus particles. {ECO:0000255|HAMAP-Rule:MF_04078}.
CC   -!- PTM: Myristoylated. {ECO:0000255|HAMAP-Rule:MF_04078}.
CC   -!- PTM: Phosphorylated on serine residues, probably by host PKCdelta and
CC       theta. {ECO:0000255|HAMAP-Rule:MF_04078}.
CC   -!- MISCELLANEOUS: HIV-1 lineages are divided in three main groups, M (for
CC       Major), O (for Outlier), and N (for New, or Non-M, Non-O). The vast
CC       majority of strains found worldwide belong to the group M. Group O
CC       seems to be endemic to and largely confined to Cameroon and neighboring
CC       countries in West Central Africa, where these viruses represent a small
CC       minority of HIV-1 strains. The group N is represented by a limited
CC       number of isolates from Cameroonian persons. The group M is further
CC       subdivided in 9 clades or subtypes (A to D, F to H, J and K).
CC       {ECO:0000255|HAMAP-Rule:MF_04078}.
CC   -!- SIMILARITY: Belongs to the lentivirus primate group Nef protein family.
CC       {ECO:0000255|HAMAP-Rule:MF_04078}.
DR   EMBL; DQ373065; ABD19500.1; -; Genomic_RNA.
DR   SMR; Q1A242; -.
DR   Proteomes; UP000008436; Genome.
DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR   GO; GO:0044178; C:host cell Golgi membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0020002; C:host cell plasma membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0016020; C:membrane; IEA:UniProtKB-UniRule.
DR   GO; GO:0019012; C:virion; IEA:UniProtKB-SubCell.
DR   GO; GO:0005525; F:GTP binding; IEA:UniProtKB-UniRule.
DR   GO; GO:0017124; F:SH3 domain binding; IEA:UniProtKB-UniRule.
DR   GO; GO:0009405; P:pathogenesis; IEA:UniProtKB-KW.
DR   GO; GO:0039504; P:suppression by virus of host adaptive immune response; IEA:UniProtKB-UniRule.
DR   GO; GO:0046776; P:suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I; IEA:UniProtKB-UniRule.
DR   GO; GO:0039505; P:suppression by virus of host antigen processing and presentation of peptide antigen via MHC class II; IEA:UniProtKB-UniRule.
DR   GO; GO:0039521; P:suppression by virus of host autophagy; IEA:UniProtKB-UniRule.
DR   Gene3D; 3.30.62.10; -; 1.
DR   Gene3D; 4.10.890.10; -; 1.
DR   HAMAP; MF_04078; NEF_HIV; 1.
DR   InterPro; IPR027480; HIV-1_Nef_anchor_sf.
DR   InterPro; IPR027481; HIV-1_Nef_core_sf.
DR   InterPro; IPR001558; HIV_Nef.
DR   Pfam; PF00469; F-protein; 1.
DR   SUPFAM; SSF55671; SSF55671; 1.
PE   3: Inferred from homology;
KW   AIDS; Apoptosis; Early protein; Host cell membrane; Host Golgi apparatus;
KW   Host membrane; Host-virus interaction;
KW   Inhibition of host adaptive immune response by virus;
KW   Inhibition of host autophagy by virus;
KW   Inhibition of host MHC class I molecule presentation by virus;
KW   Inhibition of host MHC class II molecule presentation by virus;
KW   Lipoprotein; Membrane; Myristate; Phosphoprotein; Reference proteome;
KW   Secreted; SH3-binding; Viral immunoevasion; Virion; Virulence.
FT   INIT_MET        1
FT                   /note="Removed; by host"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04078"
FT   CHAIN           2..206
FT                   /note="Protein Nef"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04078"
FT                   /id="PRO_0000440998"
FT   CHAIN           58..206
FT                   /note="C-terminal core protein"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04078"
FT                   /id="PRO_0000440999"
FT   REGION          62..66
FT                   /note="Acidic; interacts with host PACS1 and PACS2;
FT                   stabilizes the interaction of NEF/MHC-I with host AP1M1;
FT                   necessary for MHC-I internalization"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04078"
FT   REGION          69..78
FT                   /note="SH3-binding; interaction with Src family tyrosine
FT                   kinases"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04078"
FT   REGION          108..124
FT                   /note="Mediates dimerization, Nef-PTE1 interaction"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04078"
FT   REGION          148..180
FT                   /note="Binding to ATP6V1H"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04078"
FT   MOTIF           72..75
FT                   /note="PxxP; stabilizes the interaction of NEF/MHC-I with
FT                   host AP1M1; necessary for MHC-I internalization"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04078"
FT   MOTIF           164..165
FT                   /note="Dileucine internalization motif; necessary for CD4
FT                   internalization"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04078"
FT   MOTIF           174..175
FT                   /note="Diacidic; necessary for CD4 internalization"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04078"
FT   SITE            20
FT                   /note="Might play a role in AP-1 recruitment to the Nef-
FT                   MHC-I complex"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04078"
FT   SITE            57..58
FT                   /note="Cleavage; by viral protease"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04078"
FT   MOD_RES         6
FT                   /note="Phosphoserine; by host"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04078"
FT   LIPID           2
FT                   /note="N-myristoyl glycine; by host"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04078"
SQ   SEQUENCE   206 AA;  23741 MW;  FEE38FCCB833C3DA CRC64;
     MGKVWSKSSL VGWPQVIDRM RRQQDPAEGV GAVSQDLANR GAITIRNTKE NNQALAWLEE
     QKEEAVGFPV CPQVPLRPMT YKEAFDLSFF LREKGGLEGL VWSTKRQEIL DLWVYHTQGI
     FPDWQNYTPG PGVRYPLTFG WCFKLVPLSP EEVEEANQGD NNVLLHPMCQ HGMEDPDKEV
     LVWRFDSSLA RVHRARELHP EFYQNC
//
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