NEF_HV1BR
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 03-AUG-2022, entry version 174.
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; Riboviria; Pararnavirae; Artverviricota; Revtraviricetes;
OC 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; DOI=10.1128/jvi.68.5.2906-2914.1994;
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; DOI=10.1128/jvi.70.10.6701-6708.1996;
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; DOI=10.1128/jvi.72.11.8833-8840.1998;
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 impair 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 latter. 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}.
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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 PDB; 6URI; X-ray; 3.00 A; N=26-206.
DR PDBsum; 1AVV; -.
DR PDBsum; 1AVZ; -.
DR PDBsum; 1EFN; -.
DR PDBsum; 4D8D; -.
DR PDBsum; 6URI; -.
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:0044423; C:virion component; IEA:UniProtKB-UniRule.
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:0016504; F:peptidase activator activity; IDA:GO_Central.
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:0075528; P:modulation by virus of host immune response; IDA:UniProtKB.
DR GO; GO:0045225; P:negative regulation of CD4 production; 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: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 TURN 49..51
FT /evidence="ECO:0007829|PDB:6URI"
FT HELIX 53..58
FT /evidence="ECO:0007829|PDB:6URI"
FT HELIX 63..66
FT /evidence="ECO:0007829|PDB:6URI"
FT HELIX 81..93
FT /evidence="ECO:0007829|PDB:1EFN"
FT TURN 97..99
FT /evidence="ECO:0007829|PDB:1AVZ"
FT HELIX 104..118
FT /evidence="ECO:0007829|PDB:1EFN"
FT STRAND 130..132
FT /evidence="ECO:0007829|PDB:1EFN"
FT STRAND 136..138
FT /evidence="ECO:0007829|PDB:1EFN"
FT STRAND 143..147
FT /evidence="ECO:0007829|PDB:1EFN"
FT HELIX 150..156
FT /evidence="ECO:0007829|PDB:6URI"
FT HELIX 167..169
FT /evidence="ECO:0007829|PDB:6URI"
FT STRAND 170..172
FT /evidence="ECO:0007829|PDB:6URI"
FT STRAND 181..185
FT /evidence="ECO:0007829|PDB:1EFN"
FT HELIX 187..190
FT /evidence="ECO:0007829|PDB:1EFN"
FT HELIX 194..198
FT /evidence="ECO:0007829|PDB:1EFN"
FT HELIX 200..202
FT /evidence="ECO:0007829|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
