UniProtKB - Q70627 (NEF_HV1LW)
Protein Nef
nef
Functioni
Factor of infectivity and pathogenicity, required for optimal virus replication. Alters numerous pathways of T-lymphocyte function and down-regulates immunity surface molecules in order to evade host defense and increase viral infectivity. Alters the functionality of other immunity cells, like dendritic cells, monocytes/macrophages and NK cells.
UniRule annotationIn infected CD4+ T-lymphocytes, down-regulates the surface MHC-I, mature MHC-II, CD4, CD28, CCR5 and CXCR4 molecules. Mediates internalization and degradation of host CD4 through the interaction of with the cytoplasmic tail of CD4, the recruitment of AP-2 (clathrin adapter protein complex 2), internalization through clathrin coated pits, and subsequent transport to endosomes and lysosomes for degradation. Diverts host MHC-I molecules to the trans-Golgi network-associated endosomal compartments by an endocytic pathway to finally target them for degradation. MHC-I down-regulation may involve AP-1 (clathrin adapter protein complex 1) or possibly Src family kinase-ZAP70/Syk-PI3K cascade recruited by PACS2. In consequence infected cells are masked for immune recognition by cytotoxic T-lymphocytes. Decreasing the number of immune receptors also prevents reinfection by more HIV particles (superinfection). Down-regulates host SERINC3 and SERINC5 thereby excluding these proteins from the viral particles. Virion infectivity is drastically higher when SERINC3 or SERINC5 are excluded from the viral envelope, because these host antiviral proteins impair the membrane fusion event necessary for subsequent virion penetration.
UniRule annotationBypasses host T-cell signaling by inducing a transcriptional program nearly identical to that of anti-CD3 cell activation. Interaction with TCR-zeta chain up-regulates the Fas ligand (FasL). Increasing surface FasL molecules and decreasing surface MHC-I molecules on infected CD4+ cells send attacking cytotoxic CD8+ T-lymphocytes into apoptosis.
UniRule annotationPlays a role in optimizing the host cell environment for viral replication without causing cell death by apoptosis. Protects the infected cells from apoptosis in order to keep them alive until the next virus generation is ready to strike. Inhibits the Fas and TNFR-mediated death signals by blocking MAP3K5/ASK1. Decreases the half-life of TP53, protecting the infected cell against p53-mediated apoptosis. Inhibits the apoptotic signals regulated by the Bcl-2 family proteins through the formation of a Nef/PI3-kinase/PAK2 complex that leads to activation of PAK2 and induces phosphorylation of host BAD.
UniRule annotationExtracellular Nef protein targets CD4+ T-lymphocytes for apoptosis by interacting with CXCR4 surface receptors.
UniRule annotationMiscellaneous
Sites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Sitei | 20 | Might play a role in AP-1 recruitment to the Nef-MHC-I complexUniRule annotation | 1 |
GO - Molecular functioni
- ATPase binding Source: UniProtKB
- CD4 receptor binding Source: UniProtKB
- GTP binding Source: UniProtKB-UniRule
- MHC class I protein binding Source: UniProtKB
- protein kinase binding Source: UniProtKB
- SH3 domain binding Source: UniProtKB-UniRule
- signaling receptor binding Source: UniProtKB
- thioesterase binding Source: UniProtKB
GO - Biological processi
- modulation by virus of host immune response Source: UniProtKB
- negative regulation of CD4 production Source: UniProtKB
- regulation of calcium-mediated signaling Source: UniProtKB
- suppression by symbiont of host T-cell mediated immune response Source: UniProtKB
- suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Source: UniProtKB
- suppression by virus of host antigen processing and presentation of peptide antigen via MHC class II Source: UniProtKB-UniRule
- suppression by virus of host autophagy Source: UniProtKB-UniRule
- viral life cycle Source: UniProtKB
Keywordsi
Names & Taxonomyi
Protein namesi | Recommended name: Protein NefUniRule annotationAlternative name(s): 3'ORFUniRule annotation Negative factorUniRule annotation Short name: F-proteinUniRule annotation Cleaved into the following chain: C-terminal core proteinUniRule annotation |
Gene namesi | Name:nefUniRule annotation |
Organismi | Human immunodeficiency virus type 1 group M subtype B (isolate LW123) (HIV-1) |
Taxonomic identifieri | 82834 [NCBI] |
Taxonomic lineagei | Viruses › Riboviria › Pararnavirae › Artverviricota › Revtraviricetes › Ortervirales › Retroviridae › Orthoretrovirinae › Lentivirus › |
Virus hosti | Homo sapiens (Human) [TaxID: 9606] |
Subcellular locationi
- Host cell membrane UniRule annotation; Lipid-anchor UniRule annotation; Cytoplasmic side UniRule annotation
- Virion UniRule annotation
- Secreted UniRule annotation
- Host Golgi apparatus membrane UniRule annotation Note: TGN localization requires PACS1. Associates with the inner plasma membrane through its N-terminal domain. Nef stimulates its own export via the release of exosomes. Incorporated in virions at a rate of about 10 molecules per virion, where it is cleaved.UniRule annotation
Keywords - Cellular componenti
Host cell membrane, Host Golgi apparatus, Host membrane, Membrane, Secreted, VirionPTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Initiator methioninei | Removed; by hostUniRule annotation | |||
ChainiPRO_0000038325 | 2 – 206 | Protein NefUniRule annotationAdd BLAST | 205 | |
ChainiPRO_0000038326 | 58 – 206 | C-terminal core proteinUniRule annotationAdd BLAST | 149 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Lipidationi | 2 | N-myristoyl glycine; by hostUniRule annotation | 1 | |
Modified residuei | 6 | Phosphoserine; by hostUniRule annotation | 1 |
Post-translational modificationi
Sites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Sitei | 57 – 58 | Cleavage; by viral proteaseUniRule annotation | 2 |
Keywords - PTMi
Lipoprotein, Myristate, PhosphoproteinExpressioni
Inductioni
Keywords - Developmental stagei
Early proteinInteractioni
Subunit structurei
Monomer; cytosolic form. Homodimer; membrane bound form.
Interacts with Nef associated p21-activated kinase (PAK2); this interaction activates PAK2. Associates with the Nef-MHC-I-AP1 complex; this complex is required for MHC-I internalization.
Interacts (via C-terminus) with host PI3-kinase.
Interacts with host PACS1; this interaction seems to be weak.
Interacts with host PACS2.
Interacts with host LCK and MAPK3; these interactions inhibit the kinase activity of the latter.
Interacts with host ATP6V1H; this interaction may play a role in CD4 endocytosis. Associates with the CD4-Nef-AP2 complex; this complex is required for CD4 internalization.
Interacts with host AP2 subunit alpha and AP2 subunit sigma2.
Interacts with TCR-zeta chain; this interaction up-regulates the Fas ligand (FasL) surface expression.
Interacts with host HCK, LYN, and SRC; these interactions activate the Src family kinases.
Interacts with MAP3K5; this interaction inhibits the Fas and TNFR-mediated death signals.
Interacts with beta-COP and PTE1.
Interacts with human RACK1; this increases Nef phosphorylation by PKC.
Interacts with TP53; this interaction decreases the half-life of TP53, protecting the infected cell against p53-mediated apoptosis.
UniRule annotationGO - Molecular functioni
- ATPase binding Source: UniProtKB
- CD4 receptor binding Source: UniProtKB
- MHC class I protein binding Source: UniProtKB
- protein kinase binding Source: UniProtKB
- SH3 domain binding Source: UniProtKB-UniRule
- signaling receptor binding Source: UniProtKB
- thioesterase binding Source: UniProtKB
Structurei
Secondary structure
3D structure databases
SMRi | Q70627 |
ModBasei | Search... |
PDBe-KBi | Search... |
Miscellaneous databases
EvolutionaryTracei | Q70627 |
Family & Domainsi
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 62 – 65 | Acidic; interacts with host PACS1 and PACS2; stabilizes the interaction of NEF/MHC-I with host AP1M1; necessary for MHC-I internalizationUniRule annotation | 4 | |
Regioni | 69 – 78 | SH3-binding; interaction with Src family tyrosine kinasesUniRule annotation | 10 | |
Regioni | 108 – 124 | Mediates dimerization, Nef-PTE1 interactionUniRule annotationAdd BLAST | 17 | |
Regioni | 148 – 180 | Binding to ATP6V1HUniRule annotationAdd BLAST | 33 |
Motif
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Motifi | 72 – 75 | PxxP; stabilizes the interaction of NEF/MHC-I with host AP1M1; necessary for MHC-I internalizationUniRule annotation | 4 | |
Motifi | 164 – 165 | Dileucine internalization motif; necessary for CD4 internalizationUniRule annotation | 2 | |
Motifi | 174 – 175 | Diacidic; necessary for CD4 internalizationUniRule annotation | 2 |
Domaini
Sequence similaritiesi
Keywords - Domaini
SH3-bindingFamily and domain databases
DisProti | DP02888 |
Gene3Di | 3.30.62.10, 1 hit 4.10.890.10, 1 hit |
HAMAPi | MF_04078, NEF_HIV, 1 hit |
IDEALi | IID90023 |
InterProi | View protein in InterPro IPR027480, HIV-1_Nef_anchor_sf IPR027481, HIV-1_Nef_core_sf IPR001558, HIV_Nef |
Pfami | View protein in Pfam PF00469, F-protein, 1 hit |
SUPFAMi | SSF55671, SSF55671, 1 hit |
i Sequence
Sequence statusi: Complete.
: The displayed sequence is further processed into a mature form. Sequence processingi
10 20 30 40 50
MGGKWSKSSV IGWPTVRERM RRAEPAADGV GAASQDLEKH GAITSSNTAA
60 70 80 90 100
TNADCAWLEA QEEEEVGFPV TPQVPLRPMT YKAAVDLSHF LKEKGGLEGL
110 120 130 140 150
IHSQRRQDIL DLWIYHTQGY FPDWQNYTPG PGIRYPLTFG WCYKLVPVEP
160 170 180 190 200
EKLEEANKGE NTSLLHPVSL HGMDDPEREV LEWRFDSRLA FHHVARELHP
EYFKNC
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | U12055 Genomic RNA Translation: AAA76691.1 |
Similar proteinsi
Cross-referencesi
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | U12055 Genomic RNA Translation: AAA76691.1 |
3D structure databases
Select the link destinations: PDBei RCSB PDBi PDBji Links Updated | PDB entry | Method | Resolution (Å) | Chain | Positions | PDBsum |
2NEF | NMR | - | A | 56-205 | [»] | |
SMRi | Q70627 | |||||
ModBasei | Search... | |||||
PDBe-KBi | Search... |
Miscellaneous databases
EvolutionaryTracei | Q70627 |
Family and domain databases
DisProti | DP02888 |
Gene3Di | 3.30.62.10, 1 hit 4.10.890.10, 1 hit |
HAMAPi | MF_04078, NEF_HIV, 1 hit |
IDEALi | IID90023 |
InterProi | View protein in InterPro IPR027480, HIV-1_Nef_anchor_sf IPR027481, HIV-1_Nef_core_sf IPR001558, HIV_Nef |
Pfami | View protein in Pfam PF00469, F-protein, 1 hit |
SUPFAMi | SSF55671, SSF55671, 1 hit |
MobiDBi | Search... |
Entry informationi
Entry namei | NEF_HV1LW | |
Accessioni | Q70627Primary (citable) accession number: Q70627 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | July 15, 1998 |
Last sequence update: | January 23, 2007 | |
Last modified: | February 23, 2022 | |
This is version 135 of the entry and version 3 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Viral Protein Annotation Program |
Miscellaneousi
Keywords - Technical termi
3D-structureDocuments
- PDB cross-references
Index of Protein Data Bank (PDB) cross-references - SIMILARITY comments
Index of protein domains and families