ID O92593_9HIV1 Unreviewed; 211 AA. AC O92593; DT 01-NOV-1998, integrated into UniProtKB/TrEMBL. DT 01-NOV-1998, sequence version 1. DT 10-OCT-2018, entry version 81. 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:CAA77077.1}; OS Human immunodeficiency virus 1. OC Viruses; Ortervirales; Retroviridae; Orthoretrovirinae; Lentivirus. OX NCBI_TaxID=11676 {ECO:0000313|EMBL:CAA77077.1}; OH NCBI_TaxID=9606; Homo sapiens (Human). RN [1] {ECO:0000313|EMBL:CAA77077.1} RP NUCLEOTIDE SEQUENCE. RC STRAIN=3715 {ECO:0000313|EMBL:CAA77077.1}; RA Ahmad K.M., Jameel S.; RT "NEF sequences of primary hiv-1 isolates from northern India."; RL Submitted (OCT-1998) to the EMBL/GenBank/DDBJ databases. 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:SAAS01051624}. 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:SAAS01051605}. CC -!- CAUTION: Lacks conserved residue(s) required for the propagation CC of feature annotation. {ECO:0000256|HAMAP-Rule:MF_04078}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; Y18199; CAA77077.1; -; Genomic_RNA. DR ProteinModelPortal; O92593; -. 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:0030683; P:evasion or tolerance by virus of host immune response; IEA:UniProtKB-KW. DR GO; GO:0009405; P:pathogenesis; 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 2: Evidence at transcript level; KW Apoptosis {ECO:0000256|HAMAP-Rule:MF_04078}; KW Early protein {ECO:0000256|HAMAP-Rule:MF_04078}; KW Host cell membrane {ECO:0000256|HAMAP-Rule:MF_04078, KW ECO:0000256|SAAS:SAAS01051610}; KW Host Golgi apparatus {ECO:0000256|HAMAP-Rule:MF_04078}; KW Host membrane {ECO:0000256|HAMAP-Rule:MF_04078, KW ECO:0000256|SAAS:SAAS01051635}; KW Host-virus interaction {ECO:0000256|HAMAP-Rule:MF_04078, KW ECO:0000256|SAAS:SAAS01051595}; 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:SAAS01051602}; KW Myristate {ECO:0000256|HAMAP-Rule:MF_04078, KW ECO:0000256|RuleBase:RU000344}; KW Phosphoprotein {ECO:0000256|HAMAP-Rule:MF_04078}; 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 74 83 SH3-binding; interaction with Src family FT tyrosine kinases. {ECO:0000256|HAMAP- FT Rule:MF_04078}. FT REGION 113 129 Mediates dimerization, Nef-PTE1 FT interaction. {ECO:0000256|HAMAP-Rule: FT MF_04078}. FT REGION 153 185 Binding to ATP6V1H. {ECO:0000256|HAMAP- FT Rule:MF_04078}. FT MOTIF 77 80 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 169 170 Dileucine internalization motif; FT necessary for CD4 internalization. FT {ECO:0000256|HAMAP-Rule:MF_04078}. FT MOTIF 179 180 Diacidic; necessary for CD4 FT internalization. {ECO:0000256|HAMAP-Rule: FT MF_04078}. FT SITE 20 20 Might play a role in AP-1 recruitment to FT the Nef-MHC-I complex. FT {ECO:0000256|HAMAP-Rule:MF_04078}. FT SITE 61 62 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 211 AA; 24238 MW; 92AB590B99EA60A7 CRC64; MGGKWSKSSI VGWPAIRERM RRTEPAAEPA AEGVGAASQD LDRHGALTSS NTDTNNADCA WLRAQEEEEE VGFPVRPQVP LRPMTFKGAF DLSFFLKEKG GLEGLIYSKK RQEILDLWVY RTQGYFPDWQ NYTPGPGERF PLTFGWCFKL VPVDPREVEE ANEGEDNSLL HPVCQHGMED EHREVLKWKF DSQLALRHRA RELHPEFYKD C //