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Database: UniProt
Entry: P03406
LinkDB: P03406
Original site: P03406 
ID   NEF_HV1BR               Reviewed;         206 AA.
AC   P03406;
DT   21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT   23-JAN-2007, sequence version 3.
DT   17-JUN-2020, entry version 165.
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   Human immunodeficiency virus type 1 group M subtype B (isolate BRU/LAI)
OS   (HIV-1).
OC   Viruses; Ortervirales; Retroviridae; Orthoretrovirinae; Lentivirus.
OX   NCBI_TaxID=11686;
OH   NCBI_TaxID=9606; Homo sapiens (Human).
RN   [1]
RP   NUCLEOTIDE SEQUENCE.
RX   PubMed=2981635; DOI=10.1016/0092-8674(85)90303-4;
RA   Wain-Hobson S., Sonigo P., Danos O., Cole S., Alizon M.;
RT   "Nucleotide sequence of the AIDS virus, LAV.";
RL   Cell 40:9-17(1985).
RN   [2]
RP   NUCLEOTIDE SEQUENCE.
RC   STRAIN=Clone pNL4-3;
RA   Buckler C.E., Buckler-White A.J., Willey R.L., McCoy J.;
RL   Submitted (JUN-1988) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   PROTEIN SEQUENCE OF 56-68, AND CLEAVAGE BY VIRAL PROTEASE.
RX   PubMed=7835426; DOI=10.1016/0014-5793(94)01370-g;
RA   Gaedigk-Nitschko K., Schoen A., Wachinger G., Erfle V., Kohleisen B.;
RT   "Cleavage of recombinant and cell derived human immunodeficiency virus 1
RT   (HIV-1) Nef protein by HIV-1 protease.";
RL   FEBS Lett. 357:275-278(1995).
RN   [4]
RP   MYRISTOYLATION AT GLY-2, FUNCTION IN VIRULENCE, AND MUTAGENESIS OF
RP   2-GLY-GLY-3.
RC   STRAIN=Clone pNL4-3;
RX   PubMed=8151761;
RA   Chowers M.Y., Spina C.A., Kwoh T.J., Fitch N.J.S., Richman D.D.,
RA   Guatelli J.C.;
RT   "Optimal infectivity in vitro of human immunodeficiency virus type 1
RT   requires an intact nef gene.";
RL   J. Virol. 68:2906-2914(1994).
RN   [5]
RP   FUNCTION, AND DI-LEUCINE MOTIF.
RX   PubMed=8124721; DOI=10.1016/0092-8674(94)90360-3;
RA   Aiken C., Konner J., Landau N.R., Lenburg M.E., Trono D.;
RT   "Nef induces CD4 endocytosis: requirement for a critical dileucine motif in
RT   the membrane-proximal CD4 cytoplasmic domain.";
RL   Cell 76:853-864(1994).
RN   [6]
RP   SH3-BINDING REGION, AND MUTAGENESIS OF PRO-72; PRO-75; PRO-147 AND PRO-150.
RX   PubMed=7859737; DOI=10.1002/j.1460-2075.1995.tb07024.x;
RA   Saksela K., Cheng G., Baltimore D.;
RT   "Proline-rich (PxxP) motifs in HIV-1 Nef bind to SH3 domains of a subset of
RT   Src kinases and are required for the enhanced growth of Nef+ viruses but
RT   not for down-regulation of CD4.";
RL   EMBO J. 14:484-491(1995).
RN   [7]
RP   INTERACTION WITH HUMAN LCK AND HUMAN MAPK3.
RX   PubMed=8794306;
RA   Greenway A.L., Azad A., Mills J., McPhee D.A.;
RT   "Human immunodeficiency virus type 1 Nef binds directly to LCK and mitogen-
RT   activated protein kinase, inhibiting kinase activity.";
RL   J. Virol. 70:6701-6708(1996).
RN   [8]
RP   SUBCELLULAR LOCATION, AND CLEAVAGE BY VIRAL PROTEASE.
RC   STRAIN=Clone pNL4-3;
RX   PubMed=8623533; DOI=10.1006/viro.1996.0240;
RA   Welker R., Kottler H., Kalbitzer H.R., Kraeusslich H.-G.;
RT   "Human immunodeficiency virus type 1 Nef protein is incorporated into virus
RT   particles and specifically cleaved by the viral proteinase.";
RL   Virology 219:228-236(1996).
RN   [9]
RP   SUBCELLULAR LOCATION, AND N-TERMINAL DOMAIN.
RC   STRAIN=Clone pNL4-3;
RX   PubMed=9765428;
RA   Welker R., Harris M., Cardel B., Kraeusslich H.-G.;
RT   "Virion incorporation of human immunodeficiency virus type 1 Nef is
RT   mediated by a bipartite membrane-targeting signal: analysis of its role in
RT   enhancement of viral infectivity.";
RL   J. Virol. 72:8833-8840(1998).
RN   [10]
RP   FUNCTION, AND MUTAGENESIS OF MET-20.
RC   STRAIN=clone pNL-432;
RX   PubMed=10684310; DOI=10.1128/jvi.74.6.2907-2912.2000;
RA   Akari H., Arold S., Fukumori T., Okazaki T., Strebel K., Adachi A.;
RT   "Nef-induced major histocompatibility complex class I down-regulation is
RT   functionally dissociated from its virion incorporation, enhancement of
RT   viral infectivity, and CD4 down-regulation.";
RL   J. Virol. 74:2907-2912(2000).
RN   [11]
RP   FUNCTION, AND INTERACTION WITH HUMAN PAK2.
RX   PubMed=11070003; DOI=10.1128/jvi.74.23.11081-11087.2000;
RA   Arora V.K., Molina R.P., Foster J.L., Blakemore J.L., Chernoff J.,
RA   Fredericksen B.L., Garcia J.V.;
RT   "Lentivirus Nef specifically activates Pak2.";
RL   J. Virol. 74:11081-11087(2000).
RN   [12]
RP   FUNCTION.
RC   STRAIN=Clone pNL4-3;
RX   PubMed=11285224; DOI=10.1093/emboj/20.7.1593;
RA   Swigut T., Shohdy N., Skowronski J.;
RT   "Mechanism for down-regulation of CD28 by Nef.";
RL   EMBO J. 20:1593-1604(2001).
RN   [13]
RP   FUNCTION, AND INTERACTION WITH HUMAN MAP3K5.
RX   PubMed=11298454; DOI=10.1038/35071111;
RA   Geleziunas R., Xu W., Takeda K., Ichijo H., Greene W.C.;
RT   "HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential
RT   mechanism for protecting the infected host cell.";
RL   Nature 410:834-838(2001).
RN   [14]
RP   MUTAGENESIS OF THR-71.
RC   STRAIN=Clone pNL4-3;
RX   PubMed=11525746; DOI=10.1016/s0960-9822(01)00373-6;
RA   Fackler O.T., Wolf D., Weber H.O., Laffert B., D'Aloja P.,
RA   Schuler-Thurner B., Geffin R., Saksela K., Geyer M., Peterlin B.M.,
RA   Schuler G., Baur A.S.;
RT   "A natural variability in the proline-rich motif of Nef modulates HIV-1
RT   replication in primary T cells.";
RL   Curr. Biol. 11:1294-1299(2001).
RN   [15]
RP   FUNCTION, AND INTERACTION WITH HOST TP53.
RC   STRAIN=Clone pNL4-3;
RX   PubMed=11861836; DOI=10.1128/jvi.76.6.2692-2702.2002;
RA   Greenway A.L., McPhee D.A., Allen K., Johnstone R., Holloway G., Mills J.,
RA   Azad A., Sankovich S., Lambert P.;
RT   "Human immunodeficiency virus type 1 Nef binds to tumor suppressor p53 and
RT   protects cells against p53-mediated apoptosis.";
RL   J. Virol. 76:2692-2702(2002).
RN   [16]
RP   FUNCTION.
RC   STRAIN=Clone pNL4-3;
RX   PubMed=14990729; DOI=10.1128/jvi.78.6.3099-3109.2004;
RA   James C.O., Huang M.B., Khan M., Garcia-Barrio M., Powell M.D., Bond V.C.;
RT   "Extracellular Nef protein targets CD4+ T cells for apoptosis by
RT   interacting with CXCR4 surface receptors.";
RL   J. Virol. 78:3099-3109(2004).
RN   [17]
RP   FUNCTION.
RC   STRAIN=Clone pNL4-3;
RX   PubMed=14617802; DOI=10.1091/mbc.e03-08-0578;
RA   Larsen J.E., Massol R.H., Nieland T.J.F., Kirchhausen T.;
RT   "HIV Nef-mediated major histocompatibility complex class I down-modulation
RT   is independent of Arf6 activity.";
RL   Mol. Biol. Cell 15:323-331(2004).
RN   [18]
RP   FUNCTION.
RC   STRAIN=Clone pNL4-3;
RX   PubMed=15854903; DOI=10.1016/j.cub.2005.02.058;
RA   Michel N., Allespach I., Venzke S., Fackler O.T., Keppler O.T.;
RT   "The Nef protein of human immunodeficiency virus establishes superinfection
RT   immunity by a dual strategy to downregulate cell-surface CCR5 and CD4.";
RL   Curr. Biol. 15:714-723(2005).
RN   [19]
RP   FUNCTION.
RC   STRAIN=Clone pNL4-3;
RX   PubMed=16928758; DOI=10.1128/jvi.01556-06;
RA   Venzke S., Michel N., Allespach I., Fackler O.T., Keppler O.T.;
RT   "Expression of Nef downregulates CXCR4, the major coreceptor of human
RT   immunodeficiency virus, from the surfaces of target cells and thereby
RT   enhances resistance to superinfection.";
RL   J. Virol. 80:11141-11152(2006).
RN   [20]
RP   FUNCTION.
RC   STRAIN=Clone pNL4-3;
RX   PubMed=18005690; DOI=10.1016/j.chom.2007.03.004;
RA   Hung C.H., Thomas L., Ruby C.E., Atkins K.M., Morris N.P., Knight Z.A.,
RA   Scholz I., Barklis E., Weinberg A.D., Shokat K.M., Thomas G.;
RT   "HIV-1 Nef assembles a Src family kinase-ZAP-70/Syk-PI3K cascade to
RT   downregulate cell-surface MHC-I.";
RL   Cell Host Microbe 1:121-133(2007).
RN   [21]
RP   DIACIDIC MOTIF, MUTAGENESIS OF 164-LEU-LEU-165 AND 174-ASP-ASP-175, AND
RP   INTERACTION WITH HOST AP-2 COMPLEX.
RX   PubMed=18032517; DOI=10.1128/jvi.01874-07;
RA   Lindwasser O.W., Smith W.J., Chaudhuri R., Yang P., Hurley J.H.,
RA   Bonifacino J.S.;
RT   "A diacidic motif in human immunodeficiency virus type 1 Nef is a novel
RT   determinant of binding to AP-2.";
RL   J. Virol. 82:1166-1174(2008).
RN   [22]
RP   IDENTIFICATION IN A CD4-NEF-AP2 COMPLEX.
RC   STRAIN=Clone pNL4-3;
RX   PubMed=19129443; DOI=10.1128/jvi.02227-08;
RA   Chaudhuri R., Mattera R., Lindwasser O.W., Robinson M.S., Bonifacino J.S.;
RT   "A basic patch on alpha-adaptin is required for binding of human
RT   immunodeficiency virus type 1 Nef and cooperative assembly of a CD4-Nef-AP-
RT   2 complex.";
RL   J. Virol. 83:2518-2530(2009).
RN   [23]
RP   REVIEW.
RX   PubMed=25585010; DOI=10.1016/j.bbagen.2015.01.003;
RA   Pawlak E.N., Dikeakos J.D.;
RT   "HIV-1 Nef: a master manipulator of the membrane trafficking machinery
RT   mediating immune evasion.";
RL   Biochim. Biophys. Acta 1850:733-741(2015).
RN   [24]
RP   FUNCTION.
RC   STRAIN=Clone pNL4-3;
RX   PubMed=26416734; DOI=10.1038/nature15399;
RA   Rosa A., Chande A., Ziglio S., De Sanctis V., Bertorelli R., Goh S.L.,
RA   McCauley S.M., Nowosielska A., Antonarakis S.E., Luban J., Santoni F.A.,
RA   Pizzato M.;
RT   "HIV-1 Nef promotes infection by excluding SERINC5 from virion
RT   incorporation.";
RL   Nature 526:212-217(2015).
RN   [25]
RP   FUNCTION.
RC   STRAIN=Clone pNL4-3;
RX   PubMed=26416733; DOI=10.1038/nature15400;
RA   Usami Y., Wu Y., Goettlinger H.G.;
RT   "SERINC3 and SERINC5 restrict HIV-1 infectivity and are counteracted by
RT   Nef.";
RL   Nature 526:218-223(2015).
RN   [26]
RP   SUBUNIT, AND SUBCELLULAR LOCATION.
RC   STRAIN=Clone pNL4-3;
RX   PubMed=19781555; DOI=10.1016/j.jmb.2009.09.047;
RA   Poe J.A., Smithgall T.E.;
RT   "HIV-1 Nef dimerization is required for Nef-mediated receptor down-
RT   regulation and viral replication.";
RL   J. Mol. Biol. 394:329-342(2009).
RN   [27]
RP   X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 54-205 IN COMPLEX WITH A SRC
RP   FAMILY SH3 DOMAIN.
RX   PubMed=8681387; DOI=10.1016/s0092-8674(00)81276-3;
RA   Lee C.H., Saksela K., Mirza U.A., Chait B.T., Kuriyan J.;
RT   "Crystal structure of the conserved core of HIV-1 Nef complexed with a Src
RT   family SH3 domain.";
RL   Cell 85:931-942(1996).
CC   -!- FUNCTION: Factor of infectivity and pathogenicity, required for optimal
CC       virus replication (PubMed:8151761). Alters numerous pathways of T-
CC       lymphocytes function and down-regulates immunity surface molecules in
CC       order to evade host defense and increase viral infectivity
CC       (PubMed:25585010). Alters the functionality of other immunity cells,
CC       like dendritic cells, monocytes/macrophages and NK cells
CC       (PubMed:25585010). {ECO:0000255|HAMAP-Rule:MF_04078,
CC       ECO:0000269|PubMed:25585010, ECO:0000269|PubMed:8151761}.
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       ECO:0000269|PubMed:10684310, ECO:0000269|PubMed:11285224,
CC       ECO:0000269|PubMed:14617802, ECO:0000269|PubMed:15854903,
CC       ECO:0000269|PubMed:16928758, ECO:0000269|PubMed:18005690,
CC       ECO:0000269|PubMed:26416733, ECO:0000269|PubMed:26416734}.
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) (By
CC       similarity). Increasing surface FasL molecules and decreasing surface
CC       MHC-I molecules on infected CD4(+) cells send attacking cytotoxic CD8+
CC       T-lymphocytes into apoptosis (PubMed:11298454). {ECO:0000255|HAMAP-
CC       Rule:MF_04078, ECO:0000269|PubMed:11298454}.
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, ECO:0000269|PubMed:11298454,
CC       ECO:0000269|PubMed:11861836}.
CC   -!- FUNCTION: Extracellular Nef protein targets CD4(+) T-lymphocytes for
CC       apoptosis by interacting with CXCR4 surface receptors
CC       (PubMed:14990729). {ECO:0000255|HAMAP-Rule:MF_04078,
CC       ECO:0000269|PubMed:14990729}.
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, ECO:0000269|PubMed:11070003,
CC       ECO:0000269|PubMed:11298454, ECO:0000269|PubMed:11861836,
CC       ECO:0000269|PubMed:18032517, ECO:0000269|PubMed:19781555,
CC       ECO:0000269|PubMed:8794306}.
CC   -!- INTERACTION:
CC       P03406; P08631: HCK; Xeno; NbExp=2; IntAct=EBI-15672419, EBI-346340;
CC   -!- SUBCELLULAR LOCATION: Host cell membrane {ECO:0000255|HAMAP-
CC       Rule:MF_04078, ECO:0000269|PubMed:19781555}; Lipid-anchor
CC       {ECO:0000255|HAMAP-Rule:MF_04078, ECO:0000269|PubMed:19781555};
CC       Cytoplasmic side {ECO:0000255|HAMAP-Rule:MF_04078,
CC       ECO:0000269|PubMed:19781555}. Virion {ECO:0000255|HAMAP-Rule:MF_04078,
CC       ECO:0000269|PubMed:8623533, ECO:0000269|PubMed:9765428}. Secreted
CC       {ECO:0000255|HAMAP-Rule:MF_04078}. Host Golgi apparatus membrane
CC       {ECO:0000255|HAMAP-Rule:MF_04078, ECO:0000269|PubMed:19781555}.
CC       Note=TGN localization requires PACS1. Associates with the inner plasma
CC       membrane through its N-terminal domain. Nef stimulates its own export
CC       via the release of exosomes. Incorporated in virions at a rate of about
CC       10 molecules per virion, where it is cleaved. {ECO:0000255|HAMAP-
CC       Rule:MF_04078, ECO:0000269|PubMed:19781555, ECO:0000269|PubMed:8623533,
CC       ECO:0000269|PubMed:9765428}.
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, ECO:0000269|PubMed:11861836,
CC       ECO:0000269|PubMed:8151761}.
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       ECO:0000269|PubMed:7859737, ECO:0000269|PubMed:8681387}.
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       ECO:0000269|PubMed:18032517}.
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       ECO:0000269|PubMed:7835426, ECO:0000269|PubMed:8623533}.
CC   -!- PTM: Myristoylated. {ECO:0000255|HAMAP-Rule:MF_04078,
CC       ECO:0000269|PubMed:8151761}.
CC   -!- PTM: Phosphorylated on serine residues, probably by host PKCdelta and
CC       theta. {ECO:0000255|HAMAP-Rule:MF_04078}.
CC   -!- MISCELLANEOUS: The infectious clone pNL4-3 is a chimeric provirus that
CC       consists of DNA from HIV isolates NY5 (5' half) and BRU (3' half).
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; K02013; AAB59752.1; -; Genomic_RNA.
DR   EMBL; M19921; AAA44993.1; -; Genomic_RNA.
DR   EMBL; A04321; CAA00353.1; -; Unassigned_RNA.
DR   PIR; A04008; ASLJFV.
DR   PDB; 1AVV; X-ray; 3.00 A; A=58-206.
DR   PDB; 1AVZ; X-ray; 3.00 A; A/B=58-206.
DR   PDB; 1EFN; X-ray; 2.50 A; B/D=54-205.
DR   PDB; 4D8D; X-ray; 2.52 A; B/D=58-204.
DR   PDBsum; 1AVV; -.
DR   PDBsum; 1AVZ; -.
DR   PDBsum; 1EFN; -.
DR   PDBsum; 4D8D; -.
DR   SMR; P03406; -.
DR   DIP; DIP-29968N; -.
DR   ELM; P03406; -.
DR   IntAct; P03406; 1.
DR   BindingDB; P03406; -.
DR   EvolutionaryTrace; P03406; -.
DR   Proteomes; UP000007692; 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:0051117; F:ATPase binding; IPI:UniProtKB.
DR   GO; GO:0005516; F:calmodulin binding; IPI:UniProtKB.
DR   GO; GO:0042609; F:CD4 receptor binding; IPI:UniProtKB.
DR   GO; GO:0005525; F:GTP binding; IEA:UniProtKB-UniRule.
DR   GO; GO:0042288; F:MHC class I protein binding; IPI:UniProtKB.
DR   GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB.
DR   GO; GO:0017124; F:SH3 domain binding; IPI:UniProtKB.
DR   GO; GO:0005102; F:signaling receptor binding; IPI:UniProtKB.
DR   GO; GO:0031996; F:thioesterase binding; IPI:UniProtKB.
DR   GO; GO:0045225; P:negative regulation of CD4 biosynthetic process; IDA:UniProtKB.
DR   GO; GO:0009405; P:pathogenesis; IDA:UniProtKB.
DR   GO; GO:0043946; P:positive regulation of catalytic activity in other organism involved in symbiotic interaction; IDA:UniProtKB.
DR   GO; GO:0050848; P:regulation of calcium-mediated signaling; IDA:UniProtKB.
DR   GO; GO:0050863; P:regulation of T cell activation; NAS:UniProtKB.
DR   GO; GO:0052085; P:suppression by symbiont of host T-cell mediated immune response; IDA:UniProtKB.
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; IDA:UniProtKB.
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   GO; GO:0019058; P:viral life cycle; IDA:UniProtKB.
DR   DisProt; DP00048; -.
DR   Gene3D; 3.30.62.10; -; 1.
DR   Gene3D; 4.10.890.10; -; 1.
DR   HAMAP; MF_04078; NEF_HIV; 1.
DR   IDEAL; IID90018; -.
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   1: Evidence at protein level;
KW   3D-structure; AIDS; Apoptosis; Direct protein sequencing; Early protein;
KW   Host cell membrane; Host Golgi apparatus; Host membrane;
KW   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_0000038335"
FT   CHAIN           58..206
FT                   /note="C-terminal core protein"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04078"
FT                   /id="PRO_0000038336"
FT   REGION          62..65
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                   ECO:0000269|PubMed:7859737, ECO:0000269|PubMed:8681387"
FT   REGION          108..124
FT                   /note="Mediates dimerization, Nef-PTE1 interaction"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04078"
FT   REGION          108..124
FT                   /note="Mediates dimerization, Nef-PTE1 interaction, Nef-
FT                   induced CD4 and MHC-I down-regulation and enhancement of
FT                   infectivity"
FT                   /evidence="ECO:0000269|PubMed:19781555"
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                   ECO:0000269|PubMed:18032517"
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                   ECO:0000269|PubMed:7835426"
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"
FT   VARIANT         11
FT                   /note="V -> I (in strain: Clone pNL4-3)"
FT   VARIANT         15
FT                   /note="T -> A (in strain: Clone pNL4-3)"
FT   VARIANT         33
FT                   /note="A -> V (in strain: Clone pNL4-3)"
FT   VARIANT         51
FT                   /note="T -> N (in strain: Clone pNL4-3)"
FT   MUTAGEN         2..3
FT                   /note="GG->AA: 70% loss of infectivity."
FT                   /evidence="ECO:0000269|PubMed:8151761"
FT   MUTAGEN         20
FT                   /note="M->A: Amost complete loss of Nef-induced MHC-I down-
FT                   regulation."
FT                   /evidence="ECO:0000269|PubMed:10684310"
FT   MUTAGEN         20
FT                   /note="M->R: Amost complete loss of Nef-induced MHC-I down-
FT                   regulation."
FT                   /evidence="ECO:0000269|PubMed:10684310"
FT   MUTAGEN         71
FT                   /note="T->R: Increases infectivity by a factor of three."
FT                   /evidence="ECO:0000269|PubMed:11525746"
FT   MUTAGEN         72
FT                   /note="P->A: Complete loss of binding to HCK SH3 domain and
FT                   altered viral growth; when associated with P-76. No effect
FT                   on Nef-induced CD4 down-regulation."
FT                   /evidence="ECO:0000269|PubMed:7859737"
FT   MUTAGEN         75
FT                   /note="P->A: Complete loss of binding to HCK SH3 domain and
FT                   altered viral growth; when associated with P-73. No effect
FT                   on Nef-induced CD4 down-regulation."
FT                   /evidence="ECO:0000269|PubMed:7859737"
FT   MUTAGEN         147
FT                   /note="P->A: Complete loss of binding to HCK SH3 domain and
FT                   altered viral growth. No effect on Nef-induced CD4 down-
FT                   modulation."
FT                   /evidence="ECO:0000269|PubMed:7859737"
FT   MUTAGEN         150
FT                   /note="P->A: No effect."
FT                   /evidence="ECO:0000269|PubMed:7859737"
FT   MUTAGEN         164..165
FT                   /note="LL->AA: Loss of interaction with AP-2 complex."
FT                   /evidence="ECO:0000269|PubMed:18032517"
FT   MUTAGEN         174..175
FT                   /note="DD->AA: Loss of interaction with AP-2 complex."
FT                   /evidence="ECO:0000269|PubMed:18032517"
FT   HELIX           81..93
FT                   /evidence="ECO:0000244|PDB:1EFN"
FT   TURN            97..99
FT                   /evidence="ECO:0000244|PDB:1AVZ"
FT   HELIX           104..118
FT                   /evidence="ECO:0000244|PDB:1EFN"
FT   STRAND          130..132
FT                   /evidence="ECO:0000244|PDB:1EFN"
FT   STRAND          136..138
FT                   /evidence="ECO:0000244|PDB:1EFN"
FT   STRAND          143..147
FT                   /evidence="ECO:0000244|PDB:1EFN"
FT   STRAND          181..185
FT                   /evidence="ECO:0000244|PDB:1EFN"
FT   HELIX           187..190
FT                   /evidence="ECO:0000244|PDB:1EFN"
FT   HELIX           194..198
FT                   /evidence="ECO:0000244|PDB:1EFN"
FT   HELIX           200..202
FT                   /evidence="ECO:0000244|PDB:1EFN"
SQ   SEQUENCE   206 AA;  23342 MW;  77453FC80B6004F2 CRC64;
     MGGKWSKSSV VGWPTVRERM RRAEPAADGV GAASRDLEKH GAITSSNTAA TNAACAWLEA
     QEEEEVGFPV TPQVPLRPMT YKAAVDLSHF LKEKGGLEGL IHSQRRQDIL DLWIYHTQGY
     FPDWQNYTPG PGVRYPLTFG WCYKLVPVEP DKVEEANKGE NTSLLHPVSL HGMDDPEREV
     LEWRFDSRLA FHHVARELHP EYFKNC
//
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