NEF_HV1Z2
ID NEF_HV1Z2 Reviewed; 97 AA.
AC P12478;
DT 01-OCT-1989, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 03-AUG-2022, entry version 127.
DE RecName: Full=Protein Nef;
DE AltName: Full=3'ORF;
DE AltName: Full=Negative factor;
DE Short=F-protein;
DE Contains:
DE RecName: Full=C-terminal core protein;
DE Flags: Fragment;
GN Name=nef;
OS Human immunodeficiency virus type 1 group M subtype D (isolate Z2/CDC-Z34)
OS (HIV-1).
OC Viruses; Riboviria; Pararnavirae; Artverviricota; Revtraviricetes;
OC Ortervirales; Retroviridae; Orthoretrovirinae; Lentivirus.
OX NCBI_TaxID=11683;
OH NCBI_TaxID=9606; Homo sapiens (Human).
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RA Theodore T., Buckler-White A.J.;
RL Submitted (JUL-1989) to the EMBL/GenBank/DDBJ databases.
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. One of the earliest and most abundantly expressed viral
CC proteins (By similarity). {ECO:0000250}.
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) (By similarity). {ECO:0000250}.
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 (By similarity). {ECO:0000250}.
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. Interacts and decreases the
CC half-life of p53, protecting the infected cell against p53-mediated
CC apoptosis. Inhibits the apoptotic signals regulated by the Bcl-2 family
CC proteins through the formation of a Nef/PI3-kinase/PAK2 complex that
CC leads to activation of PAK2 and induces phosphorylation of Bad (By
CC similarity). {ECO:0000250}.
CC -!- FUNCTION: Extracellular Nef protein targets CD4(+) T-lymphocytes for
CC apoptosis by interacting with CXCR4 surface receptors. {ECO:0000250}.
CC -!- SUBUNIT: Homodimer (By similarity). Interacts with Nef associated p21-
CC activated kinase (PAK2); this interaction activates PAK2. Associates
CC with the Nef-MHC-I-AP1 complex; this complex is required for MHC-I
CC internalization. Interacts (via C-terminus) with host PI3-kinase (via
CC C-terminus). Interacts with host PACS1; this interaction seems to be
CC weak. Interacts with host PACS2. Interacts with host LCK and MAPK3;
CC these interactions inhibit the kinase activity of the latter. Interacts
CC with host ATP6V1H; this interaction may play a role in CD4 endocytosis.
CC Associates with the CD4-Nef-AP2 complex; this complex is required for
CC CD4 internalization. Interacts with TCR-zeta chain; this interaction
CC up-regulates the Fas ligand (FasL) surface expression. Interacts with
CC various cellular proteins including MAP3K5, beta-COP, HCK, and PTE1.
CC Interacts with human RACK1; this increases Nef phosphorylation by PKC
CC (By similarity). {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Host cell membrane {ECO:0000250}; Lipid-anchor
CC {ECO:0000250}; Cytoplasmic side {ECO:0000250}. Host cytoplasm, host
CC perinuclear region {ECO:0000250}. Virion {ECO:0000250}. Secreted
CC {ECO:0000250}. Note=Predominantly found in the paranuclear area,
CC probably in the TGN. Correct localization requires PACS1. Also
CC associates with the inner plasma membrane through its N-terminal
CC domain. Nef stimulates its own export via the release of exosomes. Also
CC incorporated in virions at a rate of about 10 molecules per virion,
CC where it is cleaved (By similarity). {ECO:0000250}.
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 p53
CC (By similarity). {ECO:0000250}.
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 (By similarity). {ECO:0000250}.
CC -!- DOMAIN: The di-leucine internalization motif and a diacidic motif seem
CC to be required for binding to AP-2. {ECO:0000250}.
CC -!- DOMAIN: The acidic region may play a stabilizing role in the formation
CC of a ternary complex between Nef, the MHC-I cytoplasmic domain, and
CC AP1M1. {ECO:0000250}.
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 (By similarity). {ECO:0000250}.
CC -!- PTM: Phosphorylated on serine residues, probably by host PKC.
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 -!- SIMILARITY: Belongs to the lentivirus primate group Nef protein family.
CC {ECO:0000305}.
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DR EMBL; M22639; AAA45371.1; -; Genomic_RNA.
DR PIR; S54385; S54385.
DR PDB; 5EO0; X-ray; 1.70 A; C=78-86.
DR PDB; 5EO1; X-ray; 1.85 A; C=78-86.
DR PDBsum; 5EO0; -.
DR PDBsum; 5EO1; -.
DR SMR; P12478; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0044220; C:host cell perinuclear region of cytoplasm; 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 Gene3D; 3.30.62.10; -; 1.
DR Gene3D; 4.10.890.10; -; 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 3D-structure; AIDS; Apoptosis; Early protein; Host cell membrane;
KW Host cytoplasm; Host membrane; Host-virus interaction; Lipoprotein;
KW Membrane; Myristate; Phosphoprotein; Secreted; SH3-binding;
KW Viral immunoevasion; Virion; Virulence.
FT INIT_MET 1
FT /note="Removed; by host"
FT /evidence="ECO:0000250"
FT CHAIN 2..>97
FT /note="Protein Nef"
FT /id="PRO_0000038329"
FT CHAIN 58..>97
FT /note="C-terminal core protein"
FT /evidence="ECO:0000250"
FT /id="PRO_0000038330"
FT REGION 2..57
FT /note="N-terminal; associates with the host plasma
FT membrane"
FT /evidence="ECO:0000250"
FT REGION 7..26
FT /note="Necessary for MHC-I internalization"
FT /evidence="ECO:0000250"
FT REGION 62..66
FT /note="Acidic; stabilizes the interaction of NEF/MHC-I with
FT host AP1M1; necessary for MHC-I internalization and
FT interaction with host PACS1 and PACS2"
FT /evidence="ECO:0000250"
FT REGION 70..79
FT /note="SH3-binding; interaction with Src family tyrosine
FT kinases"
FT /evidence="ECO:0000250"
FT MOTIF 73..76
FT /note="PxxP; stabilizes the interaction of NEF/MHC-I with
FT host AP1M1; necessary for MHC-I internalization"
FT /evidence="ECO:0000250"
FT SITE 57..58
FT /note="Cleavage; by viral protease"
FT /evidence="ECO:0000250"
FT LIPID 2
FT /note="N-myristoyl glycine; by host"
FT /evidence="ECO:0000250"
FT NON_TER 97
SQ SEQUENCE 97 AA; 10592 MW; F8529A069B670AE9 CRC64;
MGGRWSKSSI VGWPAIRERI RRTDPAADGV GAVSRDLEKH GAITSSNTRG TNADCAWLEA
QEESEEVGFP VRPQVPLRPM TYKGALDLSH FLKEKGG
