NEF_HV1LA
ID NEF_HV1LA Reviewed; 202 AA.
AC Q9QPN3;
DT 13-SEP-2004, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 25-MAY-2022, entry version 125.
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};
DE Flags: Fragment;
GN Name=nef {ECO:0000255|HAMAP-Rule:MF_04078};
OS Human immunodeficiency virus type 1 group M subtype B (isolate Lai)
OS (HIV-1).
OC Viruses; Riboviria; Pararnavirae; Artverviricota; Revtraviricetes;
OC Ortervirales; Retroviridae; Orthoretrovirinae; Lentivirus.
OX NCBI_TaxID=290579;
OH NCBI_TaxID=9606; Homo sapiens (Human).
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Piedade J., Esteves A., Parreira R., Venenno T., Barros M.F.,
RA Canas-Ferreira W.F.;
RL Submitted (JUL-1999) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP INTERACTION WITH HUMAN BETA-COP.
RX PubMed=7982906; DOI=10.1016/s0021-9258(18)43773-8;
RA Benichou S., Bomsel M., Bodeus M., Durand H., Doute M., Letourneur F.,
RA Camonis J., Benarous R.;
RT "Physical interaction of the HIV-1 Nef protein with beta-COP, a component
RT of non-clathrin-coated vesicles essential for membrane traffic.";
RL J. Biol. Chem. 269:30073-30076(1994).
RN [3]
RP INTERACTION WITH HUMAN PTE1, AND MUTANT NEF*4.
RX PubMed=9153233; DOI=10.1074/jbc.272.21.13779;
RA Liu L.X., Margottin F., Le Gall S., Schwartz O., Selig L., Benarous R.,
RA Benichou S.;
RT "Binding of HIV-1 Nef to a novel thioesterase enzyme correlates with Nef-
RT mediated CD4 down-regulation.";
RL J. Biol. Chem. 272:13779-13785(1997).
RN [4]
RP FUNCTION, HOMODIMERIZATION, AND MUTAGENESIS OF TRP-57; ASP-108; ASP-111;
RP LEU-112; PHE-121; PRO-122; ASP-123; TRP-124 AND ASN-126.
RX PubMed=10799608; DOI=10.1128/jvi.74.11.5310-5319.2000;
RA Liu L.X., Heveker N., Fackler O.T., Arold S., Le Gall S., Janvier K.,
RA Peterlin B.M., Dumas C., Schwartz O., Benichou S., Benarous R.;
RT "Mutation of a conserved residue (D123) required for oligomerization of
RT human immunodeficiency virus type 1 Nef protein abolishes interaction with
RT human thioesterase and results in impairment of Nef biological functions.";
RL J. Virol. 74:5310-5319(2000).
RN [5]
RP FUNCTION, AND MUTAGENESIS OF 154-GLU-GLU-155; 164-LEU-LEU-165 AND
RP 174-ASP-ASP-175.
RX PubMed=11264386; DOI=10.1128/jvi.75.8.3971-3976.2001;
RA Janvier K., Craig H., Le Gall S., Benarous R., Guatelli J., Schwartz O.,
RA Benichou S.;
RT "Nef-induced CD4 down-regulation: a diacidic sequence in human
RT immunodeficiency virus type 1 Nef does not function as a protein sorting
RT motif through direct binding to beta-COP.";
RL J. Virol. 75:3971-3976(2001).
CC -!- FUNCTION: Factor of infectivity and pathogenicity, required for optimal
CC virus replication. Alters numerous pathways of T-lymphocyte 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 impair 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 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}.
CC -!- INTERACTION:
CC Q9QPN3; P50570: DNM2; Xeno; NbExp=4; IntAct=EBI-7355146, EBI-346547;
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}.
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DR EMBL; AF166101; AAD47831.1; -; Genomic_DNA.
DR SMR; Q9QPN3; -.
DR DIP; DIP-45114N; -.
DR IntAct; Q9QPN3; 1.
DR MINT; Q9QPN3; -.
DR ABCD; Q9QPN3; 3 sequenced antibodies.
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-KW.
DR GO; GO:0005525; F:GTP binding; IEA:InterPro.
DR GO; GO:0017124; F:SH3 domain binding; IEA:UniProtKB-KW.
DR GO; GO:0046776; P:suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I; IEA:UniProtKB-KW.
DR GO; GO:0039505; P:suppression by virus of host antigen processing and presentation of peptide antigen via MHC class II; IEA:UniProtKB-KW.
DR GO; GO:0039521; P:suppression by virus of host autophagy; IEA:UniProtKB-KW.
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 1: Evidence at protein level;
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; Secreted; SH3-binding;
KW Viral immunoevasion; Virion; Virulence.
FT INIT_MET 1
FT /note="Removed; by host"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04078"
FT CHAIN 2..202
FT /note="Protein Nef"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04078"
FT /id="PRO_0000038323"
FT CHAIN 58..202
FT /note="C-terminal core protein"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04078"
FT /id="PRO_0000038324"
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 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"
FT MUTAGEN 57
FT /note="W->R: In Nef*4; complete loss of Nef-induced CD4
FT down-regulation."
FT /evidence="ECO:0000269|PubMed:10799608"
FT MUTAGEN 68
FT /note="F->S: In Nef*4."
FT MUTAGEN 108
FT /note="D->A: Complete loss of Nef-PTE1 interaction and Nef-
FT induced CD4 down-modulation."
FT /evidence="ECO:0000269|PubMed:10799608"
FT MUTAGEN 111
FT /note="D->G: Complete loss of Nef-PTE1 interaction and Nef-
FT induced CD4 down-modulation."
FT /evidence="ECO:0000269|PubMed:10799608"
FT MUTAGEN 112
FT /note="L->D: Complete loss of Nef-PTE1 interaction and Nef-
FT induced CD4 down-modulation."
FT /evidence="ECO:0000269|PubMed:10799608"
FT MUTAGEN 121
FT /note="F->G: Complete loss of Nef-PTE1 interaction and Nef-
FT induced CD4 down-modulation."
FT /evidence="ECO:0000269|PubMed:10799608"
FT MUTAGEN 122
FT /note="P->R: Complete loss of Nef-PTE1 interaction and Nef-
FT induced CD4 down-modulation."
FT /evidence="ECO:0000269|PubMed:10799608"
FT MUTAGEN 123
FT /note="D->G: In Nef*4; complete loss of Nef-PTE1
FT interaction, Nef-induced CD4 and MHC-I down-regulation and
FT enhancement of infectivity."
FT /evidence="ECO:0000269|PubMed:10799608"
FT MUTAGEN 123
FT /note="D->V: Complete loss of Nef-PTE1 interaction and Nef-
FT induced CD4 down-modulation."
FT /evidence="ECO:0000269|PubMed:10799608"
FT MUTAGEN 124
FT /note="W->R: Complete loss of Nef-PTE1 interaction and Nef-
FT induced CD4 down-modulation."
FT /evidence="ECO:0000269|PubMed:10799608"
FT MUTAGEN 126
FT /note="N->S: No effect."
FT /evidence="ECO:0000269|PubMed:10799608"
FT MUTAGEN 154..155
FT /note="EE->GG: No effect on beta-COP interaction."
FT /evidence="ECO:0000269|PubMed:11264386"
FT MUTAGEN 164..165
FT /note="LL->AA: Complete loss of CD4 down-modulation; no
FT effect on beta-COP interaction."
FT /evidence="ECO:0000269|PubMed:11264386"
FT MUTAGEN 166
FT /note="H->R: In Nef*4."
FT MUTAGEN 170
FT /note="L->Q: In Nef*4."
FT MUTAGEN 174..175
FT /note="DD->AA: Complete loss of CD4 down-modulation; no
FT effect on beta-COP interaction."
FT /evidence="ECO:0000269|PubMed:11264386"
FT NON_TER 202
SQ SEQUENCE 202 AA; 23033 MW; CD61DFA6F386CC89 CRC64;
MGGKWSKSSV VGWPAVRERM RRAEPAADGV GAVSRDLEKH GAITSSNTAA TNADCAWLEA
QEEEEVGFPV TPQVPLRPMT YKAAVDLSHF LKEKGGLEGL IHSQRRQDIL DLWIYHTQGY
FPDWQNYTPE PGVRYPLTFG WCYKLVPVEP DKVEEANKGE NTRLLHPVSL HGMDDPEREV
LEWRFDSRLA FHHVARELHP EY
