ID   Q9Q6V7_9HIV1            Unreviewed;       202 AA.
AC   Q9Q6V7;
DT   01-MAY-2000, integrated into UniProtKB/TrEMBL.
DT   01-MAY-2000, sequence version 1.
DT   28-MAR-2018, entry version 83.
DE   RecName: Full=Protein Nef {ECO:0000256|HAMAP-Rule:MF_04078};
DE   AltName: Full=3'ORF {ECO:0000256|HAMAP-Rule:MF_04078};
DE   AltName: Full=Negative factor {ECO:0000256|HAMAP-Rule:MF_04078};
DE            Short=F-protein {ECO:0000256|HAMAP-Rule:MF_04078};
DE   Contains:
DE     RecName: Full=C-terminal core protein {ECO:0000256|HAMAP-Rule:MF_04078};
GN   Name=nef {ECO:0000256|HAMAP-Rule:MF_04078,
GN   ECO:0000313|EMBL:AAF22322.1};
OS   HIV-1 CRF03_AB.
OC   Viruses; Retro-transcribing viruses; Retroviridae; Orthoretrovirinae;
OC   Lentivirus; Primate lentivirus group.
OX   NCBI_TaxID=540995 {ECO:0000313|EMBL:AAF22322.1, ECO:0000313|Proteomes:UP000107373};
RN   [1] {ECO:0000313|EMBL:AAF22322.1, ECO:0000313|Proteomes:UP000107373}
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=KAL153 {ECO:0000313|EMBL:AAF22322.1};
RX   PubMed=10933619; DOI=10.1089/08892220050075309;
RA   Liitsola K., Holm K., Bobkov A., Pokrovsky V., Smolskaya T.,
RA   Leinikki P., Osmanov S., Salminen M.;
RT   "An AB recombinant and its parental HIV type 1 strains in the area of
RT   the former Soviet Union: low requirements for sequence identity in
RT   recombination. UNAIDS Virus Isolation Network.";
RL   AIDS Res. Hum. Retroviruses 16:1047-1053(2000).
CC   -!- FUNCTION: Bypasses host T-cell signaling by inducing a
CC       transcriptional program nearly identical to that of anti-CD3 cell
CC       activation. Interaction with TCR-zeta chain up-regulates the Fas
CC       ligand (FasL). Increasing surface FasL molecules and decreasing
CC       surface MHC-I molecules on infected CD4(+) cells send attacking
CC       cytotoxic CD8+ T-lymphocytes into apoptosis. {ECO:0000256|HAMAP-
CC       Rule:MF_04078}.
CC   -!- FUNCTION: Extracellular Nef protein targets CD4(+) T-lymphocytes
CC       for apoptosis by interacting with CXCR4 surface receptors.
CC       {ECO:0000256|HAMAP-Rule:MF_04078}.
CC   -!- FUNCTION: Factor of infectivity and pathogenicity, required for
CC       optimal virus replication. Alters numerous pathways of T-
CC       lymphocytes function and down-regulates immunity surface molecules
CC       in order to evade host defense and increase viral infectivity.
CC       Alters the functionality of other immunity cells, like dendritic
CC       cells, monocytes/macrophages and NK cells. {ECO:0000256|HAMAP-
CC       Rule:MF_04078}.
CC   -!- FUNCTION: In infected CD4(+) T-lymphocytes, down-regulates the
CC       surface MHC-I, mature MHC-II, CD4, CD28, CCR5 and CXCR4 molecules.
CC       Mediates internalization and degradation of host CD4 through the
CC       interaction of with the cytoplasmic tail of CD4, the recruitment
CC       of AP-2 (clathrin adapter protein complex 2), internalization
CC       through clathrin coated pits, and subsequent transport to
CC       endosomes and lysosomes for degradation. Diverts host MHC-I
CC       molecules to the trans-Golgi network-associated endosomal
CC       compartments by an endocytic pathway to finally target them for
CC       degradation. MHC-I down-regulation may involve AP-1 (clathrin
CC       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-
CC       lymphocytes. Decreasing the number of immune receptors also
CC       prevents reinfection by more HIV particles (superinfection). Down-
CC       regulates host SERINC3 and SERINC5 thereby excluding these
CC       proteins from the viral particles. Virion infectivity is
CC       drastically higher when SERINC3 or SERINC5 are excluded from the
CC       viral envelope, because these host antiviral proteins impare the
CC       membrane fusion event necessary for subsequent virion penetration.
CC       {ECO:0000256|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.
CC       Protects the infected cells from apoptosis in order to keep them
CC       alive until the next virus generation is ready to strike. Inhibits
CC       the Fas and TNFR-mediated death signals by blocking MAP3K5/ASK1.
CC       Decreases the half-life of TP53, protecting the infected cell
CC       against p53-mediated apoptosis. Inhibits the apoptotic signals
CC       regulated by the Bcl-2 family proteins through the formation of a
CC       Nef/PI3-kinase/PAK2 complex that leads to activation of PAK2 and
CC       induces phosphorylation of host BAD. {ECO:0000256|HAMAP-
CC       Rule:MF_04078}.
CC   -!- SUBUNIT: Homodimer. {ECO:0000256|SAAS:SAAS00536203}.
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
CC       complex; this complex is required for MHC-I internalization.
CC       Interacts (via C-terminus) with host PI3-kinase. Interacts with
CC       host PACS1; this interaction seems to be weak. Interacts with host
CC       PACS2. Interacts with host LCK and MAPK3; these interactions
CC       inhibit the kinase activity of the latters. Interacts with host
CC       ATP6V1H; this interaction may play a role in CD4 endocytosis.
CC       Associates with the CD4-Nef-AP2 complex; this complex is required
CC       for CD4 internalization. Interacts with host AP2 subunit alpha and
CC       AP2 subunit sigma2. Interacts with TCR-zeta chain; this
CC       interaction up-regulates the Fas ligand (FasL) surface expression.
CC       Interacts with host HCK, LYN, and SRC; these interactions activate
CC       the Src family kinases. Interacts with MAP3K5; this interaction
CC       inhibits the Fas and TNFR-mediated death signals. Interacts with
CC       beta-COP and PTE1. Interacts with human RACK1; this increases Nef
CC       phosphorylation by PKC. Interacts with TP53; this interaction
CC       decreases the half-life of TP53, protecting the infected cell
CC       against p53-mediated apoptosis. {ECO:0000256|HAMAP-Rule:MF_04078}.
CC   -!- SUBCELLULAR LOCATION: Host cell membrane {ECO:0000256|HAMAP-
CC       Rule:MF_04078}; Lipid-anchor {ECO:0000256|HAMAP-Rule:MF_04078};
CC       Cytoplasmic side {ECO:0000256|HAMAP-Rule:MF_04078}. Virion
CC       {ECO:0000256|HAMAP-Rule:MF_04078}. Secreted {ECO:0000256|HAMAP-
CC       Rule:MF_04078}. Host Golgi apparatus membrane {ECO:0000256|HAMAP-
CC       Rule:MF_04078}. Note=TGN localization requires PACS1. Associates
CC       with the inner plasma membrane through its N-terminal domain. Nef
CC       stimulates its own export via the release of exosomes.
CC       Incorporated in virions at a rate of about 10 molecules per
CC       virion, where it is cleaved. {ECO:0000256|HAMAP-Rule:MF_04078}.
CC   -!- INDUCTION: Expressed early in the viral replication cycle.
CC       {ECO:0000256|HAMAP-Rule:MF_04078}.
CC   -!- DOMAIN: The N-terminal domain is composed of the N-myristoyl
CC       glycine and of a cluster of positively charged amino acids. It is
CC       required for inner plasma membrane targeting of Nef and virion
CC       incorporation, and thereby for infectivity. This domain is also
CC       involved in binding to TP53. {ECO:0000256|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
CC       association with MAPK3, PI3-kinase and TCR-zeta.
CC       {ECO:0000256|HAMAP-Rule:MF_04078}.
CC   -!- DOMAIN: The acidic region binds to the sorting protein PACS-2,
CC       which targets Nef to the paranuclear region, enabling the PxxP
CC       motif to direct assembly of an SFK/ZAP-70/PI3K complex that
CC       accelerates endocytosis of cell-surface MHC-I. {ECO:0000256|HAMAP-
CC       Rule:MF_04078}.
CC   -!- DOMAIN: The dileucine internalization motif and a diacidic motif
CC       seem to be required for binding to AP-2. {ECO:0000256|HAMAP-
CC       Rule:MF_04078}.
CC   -!- PTM: Myristoylated. {ECO:0000256|HAMAP-Rule:MF_04078}.
CC   -!- PTM: Phosphorylated on serine residues, probably by host PKCdelta
CC       and theta. {ECO:0000256|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:0000256|HAMAP-Rule:MF_04078}.
CC   -!- MISCELLANEOUS: HIV-1 lineages are divided in three main groups, M
CC       (for Major), O (for Outlier), and N (for New, or Non-M, Non-O).
CC       The vast majority of strains found worldwide belong to the group
CC       M. Group O seems to be endemic to and largely confined to Cameroon
CC       and neighboring countries in West Central Africa, where these
CC       viruses represent a small minority of HIV-1 strains. The group N
CC       is represented by a limited number of isolates from Cameroonian
CC       persons. The group M is further subdivided in 9 clades or subtypes
CC       (A to D, F to H, J and K). {ECO:0000256|HAMAP-Rule:MF_04078}.
CC   -!- SIMILARITY: Belongs to the lentivirus primate group Nef protein
CC       family. {ECO:0000256|HAMAP-Rule:MF_04078,
CC       ECO:0000256|RuleBase:RU000344, ECO:0000256|SAAS:SAAS00536190}.
CC   -!- CAUTION: Lacks conserved residue(s) required for the propagation
CC       of feature annotation. {ECO:0000256|HAMAP-Rule:MF_04078}.
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DR   EMBL; AF193276; AAF22322.1; -; Genomic_DNA.
DR   ProteinModelPortal; Q9Q6V7; -.
DR   Proteomes; UP000107373; 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   2: Evidence at transcript level;
KW   Apoptosis {ECO:0000256|HAMAP-Rule:MF_04078};
KW   Complete proteome {ECO:0000313|Proteomes:UP000107373};
KW   Early protein {ECO:0000256|HAMAP-Rule:MF_04078};
KW   Host cell membrane {ECO:0000256|HAMAP-Rule:MF_04078,
KW   ECO:0000256|SAAS:SAAS00004523};
KW   Host Golgi apparatus {ECO:0000256|HAMAP-Rule:MF_04078};
KW   Host membrane {ECO:0000256|HAMAP-Rule:MF_04078,
KW   ECO:0000256|SAAS:SAAS00118235};
KW   Host-virus interaction {ECO:0000256|HAMAP-Rule:MF_04078,
KW   ECO:0000256|SAAS:SAAS00004502};
KW   Inhibition of host adaptive immune response by virus
KW   {ECO:0000256|HAMAP-Rule:MF_04078};
KW   Inhibition of host autophagy by virus {ECO:0000256|HAMAP-
KW   Rule:MF_04078};
KW   Inhibition of host MHC class I molecule presentation by virus
KW   {ECO:0000256|HAMAP-Rule:MF_04078};
KW   Inhibition of host MHC class II molecule presentation by virus
KW   {ECO:0000256|HAMAP-Rule:MF_04078};
KW   Lipoprotein {ECO:0000256|HAMAP-Rule:MF_04078,
KW   ECO:0000256|RuleBase:RU000344};
KW   Membrane {ECO:0000256|HAMAP-Rule:MF_04078,
KW   ECO:0000256|SAAS:SAAS00004519};
KW   Myristate {ECO:0000256|HAMAP-Rule:MF_04078,
KW   ECO:0000256|RuleBase:RU000344};
KW   Phosphoprotein {ECO:0000256|HAMAP-Rule:MF_04078};
KW   Reference proteome {ECO:0000313|Proteomes:UP000107373};
KW   Secreted {ECO:0000256|HAMAP-Rule:MF_04078};
KW   SH3-binding {ECO:0000256|HAMAP-Rule:MF_04078};
KW   Viral immunoevasion {ECO:0000256|HAMAP-Rule:MF_04078,
KW   ECO:0000256|RuleBase:RU000344};
KW   Virion {ECO:0000256|HAMAP-Rule:MF_04078};
KW   Virulence {ECO:0000256|HAMAP-Rule:MF_04078,
KW   ECO:0000256|RuleBase:RU000344}.
FT   INIT_MET      1      1       Removed; by host. {ECO:0000256|HAMAP-
FT                                Rule:MF_04078}.
FT   REGION       63     66       Acidic; interacts with host PACS1 and
FT                                PACS2; stabilizes the interaction of
FT                                NEF/MHC-I with host AP1M1; necessary for
FT                                MHC-I internalization.
FT                                {ECO:0000256|HAMAP-Rule:MF_04078}.
FT   REGION       70     79       SH3-binding; interaction with Src family
FT                                tyrosine kinases. {ECO:0000256|HAMAP-
FT                                Rule:MF_04078}.
FT   REGION      109    125       Mediates dimerization, Nef-PTE1
FT                                interaction. {ECO:0000256|HAMAP-Rule:
FT                                MF_04078}.
FT   REGION      144    176       Binding to ATP6V1H. {ECO:0000256|HAMAP-
FT                                Rule:MF_04078}.
FT   MOTIF        73     76       PxxP; stabilizes the interaction of
FT                                NEF/MHC-I with host AP1M1; necessary for
FT                                MHC-I internalization.
FT                                {ECO:0000256|HAMAP-Rule:MF_04078}.
FT   MOTIF       160    161       Dileucine internalization motif;
FT                                necessary for CD4 internalization.
FT                                {ECO:0000256|HAMAP-Rule:MF_04078}.
FT   MOTIF       170    171       Diacidic; necessary for CD4
FT                                internalization. {ECO:0000256|HAMAP-Rule:
FT                                MF_04078}.
FT   SITE         58     59       Cleavage; by viral protease.
FT                                {ECO:0000256|HAMAP-Rule:MF_04078}.
FT   MOD_RES       6      6       Phosphoserine; by host.
FT                                {ECO:0000256|HAMAP-Rule:MF_04078}.
FT   LIPID         2      2       N-myristoyl glycine; by host.
FT                                {ECO:0000256|HAMAP-Rule:MF_04078}.
SQ   SEQUENCE   202 AA;  23020 MW;  3B9EFBA099C97D93 CRC64;
     MGGKWSKSSI VGWPQVRERI RRAPAPAARG VGPVSQDLDK YGAVTSSNTA ANNADCAWLE
     AQEEEEVGFP VRPQVPLRPM TYKGAFDLSH FLKEKGGLDG LIYSKKRQEI LDLWVYHTQG
     YFPDWQPGIR FPLTFGWCYK LVPVDPAEVE EATEGENNSL LHPICQHGMD DEEKEVLMWK
     FDSRLALTHR ARELHPEFYK DC
//