Reviewed,
UniProtKB/Swiss-Prot P04601 (NEF_HV1H2)
Last modified
November 24, 2009.
Version 85.
History...
Clusters with 100%,
90%,
50% identity |
 Documents (1) |
 Third-party data |
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Names and origin
| Protein names | Recommended name: Truncated Nef protein Alternative name(s): Negative factor Short name=F-protein 3'ORF Cleaved into the following chain: 1- Recommended name: C-terminal core protein | ||
| Gene names |
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| Organism | Human immunodeficiency virus type 1 (isolate HXB2 group M subtype B) (HIV-1) | ||
| Taxonomic identifier | 11706 [NCBI] | ||
| Taxonomic lineage | Viruses › Retro-transcribing viruses › Retroviridae › Orthoretrovirinae › Lentivirus › Primate lentivirus group | ||
| Virus host | Homo sapiens (Human) [TaxID: 9606] |
Protein attributes
| Sequence length | 123 AA. |
| Sequence status | Complete. |
| Sequence processing | The displayed sequence is further processed into a mature form. |
| Protein existence | Evidence at protein level. |
General annotation (Comments)
| Function | Early protein that seems to play a role in optimizing the host cell environment for viral replication without causing cell death by apoptosis By similarity. Enhances virus infectivity and pathogenicity. Down-modulates surface MHC-I molecules through the PI3-kinase-mediated ARF6 endosomal pathway. Combines with PACS1 and accelerates the ARF6-dependent internalization of MHC-I molecules. Internalized molecules are sequestred to the trans-Golgi network (TGN). Also decreases cell surface CD4 antigen by interacting with the Src family kinase LCK thereby inducing LCK-CD4 dissociation and by increasing clathrin-dependent endocytosis of this antigen to target it to lysosomal degradation. Peroxisomal acyl-coenzyme A thioester hydrolase 1 (PTE1) seems to be involved in this process By similarity. May serve as a direct bridge between CD4 and the cellular endocytic machinery by interacting with beta-COP and adaptins. In consequence, surface MHC-I and CD4 are decreased and infected cells are masked for immune recognition by cytotoxic T lymphocytes. Decreasing the number of viral receptors prevents reinfection by more HIV particles. Bypasses host T-cell signaling by inducing a transcriptional program nearly identical to that of anti-CD3 cell activation. Interacts with the TCR-zeta chain to up-regulate the Fas ligand (FasL). Increasing surface FasL molecules and decreasing surface MHC-I molecules send attacking cytotoxic T-cell into apoptosis By similarity. Protects the infected cell from apoptosis in order to keep it alive until the next virus generation is ready to strike. Inhibits the Fas and TNFR-mediated death signals by blocking MAP3K5. Interacts with p53 and decreases the half-life of the latter, 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 induces phosphorylation of Bad By similarity. |
| Subunit structure | Homodimer. Interacts with various cellular proteins including MAP3K5, beta-COP, PAK2, PACS1, the Src family kinases HCK and LCK, TCR-zeta chain, PTE1 and PI3-kinase. Interaction with PI3-kinase activates the Nef associated p21-activated kinase (PAK2) and leads to increased production of HIV-1. This interaction depends on the C-terminus of both proteins. Interacts and inhibits kinase activity of LCK and MAPK3. Binds to ATP6V1H, this interaction connects Nef to the endocytic machinery and facilitates the internalization of CD4 By similarity. |
| Subcellular location | Host cell membrane; Lipid-anchor; Cytoplasmic side By similarity. Host cytoplasm › host perinuclear region By similarity. Virion By similarity. Note: Associates with the inner plasma membrane through its N-terminal anchor domain. Also found in the paranuclear area, probably in the TGN. Correct localization requires PACS1. Also incorporated in virions at a rate of about 10 molecules per virion, where it is cleaved By similarity. |
| Domain | The N-terminal anchor domain is composed of the N-myristoyl glycine and of a cluster of positively charged amino acids. It is required for inner plasma membrane targeting of Nef and virion incorporation, and thereby for infectivity. This domain is also involved in binding to p53 By similarity. The acidic cluster contains sorting information as it binds to the TGN sorting protein PACS1. The SH3-binding domain constituted of PxxP motifs mediates binding to several Src family proteins thereby regulating their tyrosine kinase activity. The same motifs also mediates the association with MAPK3, PI3-kinase and TCR-zeta By similarity. |
| Post-translational modification | The virion-associated Nef proteins are cleaved by the viral protease to release the soluble C-terminal core protein. Nef is probably cleaved concomitantly with viral structural proteins on maturation of virus particles By similarity. Myristoylation is essential for inner plasma membrane targeting of Nef and virion incorporation and thereby for infectivity. Also required to reduce CD4 expression at the cell surface By similarity. Phosphorylated on serine residues, probably by host PKC By similarity. |
| Miscellaneous | In this isolate a mutation in position 125 adds a stop codon and the protein is much shorter than in other isolates (210 AA). HIV-1 lineages are divided in three main groups, M (for Major), O (for Outlier), and N (for New, or Non-M, Non-O). The vast majority of strains found worldwide belong to the group M. Group O seems to be endemic to and largely confined to Cameroon and neighboring countries in West Central Africa, where these viruses represent a small minority of HIV-1 strains. The group N is represented by a limited number of isolates from Cameroonian persons. The group M is further subdivided in 9 clades or subtypes (A to D, F to H, J and K). |
| Sequence similarities | Belongs to the lentivirus primate group Nef protein family. |
| Caution | In clone pNL4-3 (AC P03406), it has been show that down-modulation of surface MHC class I molecules is independent of ARF6 endosomal pathway. |
Ontologies
Sequence annotation (Features)
| Feature key | Position(s) | Length | Description | Graphical view | Feature identifier | ||||
Molecule processing | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Initiator methionine | 1 | 1 | Removed; by host By similarity | ||||||
| Chain | 2 – 123 | 122 | Truncated Nef protein By similarity | PRO_0000038365 | |||||
| Chain | 58 – 123 | 66 | C-terminal core protein By similarity | PRO_0000038366 | |||||
Regions | |||||||||
| Repeat | 69 – 71 | 3 | 1 | ||||||
| Repeat | 72 – 74 | 3 | 2 | ||||||
| Repeat | 75 – 77 | 3 | 3 | ||||||
| Repeat | 78 – 80 | 3 | 4 | ||||||
| Region | 2 – 57 | 56 | Anchor By similarity | ||||||
| Region | 62 – 65 | 4 | Acidic cluster | ||||||
| Region | 69 – 80 | 12 | 4 X 3 AA tandem repeats of P-X-X | ||||||
| Region | 108 – 123 | 16 | Mediates dimerization, Nef-PTE1 interaction, Nef-induced CD4 and MHC-I down-modulation and enhancement of infectivity By similarity | ||||||
| Motif | 69 – 78 | 10 | SH3-binding By similarity | ||||||
Sites | |||||||||
| Site | 20 | 1 | Involved in reducing surface MHC-I molecules by both impeding cell surface retrieval of MHC-I molecules and diverting them instead to the TGN | ||||||
| Site | 57 – 58 | 2 | Cleavage; by viral protease By similarity | ||||||
Amino acid modifications | |||||||||
| Lipidation | 2 | 1 | N-myristoyl glycine; by host By similarity | ||||||
Experimental info | |||||||||
| Mutagenesis | 20 | 1 | M → A: Complete loss of Nef-induced MHC-I down-modulation, MHC-I is internalized but not sequestred in TGN. Ref.7 | ||||||
| Mutagenesis | 62 – 65 | 4 | EEEE → AAAA: Complete loss of Nef-induced MHC-I down-modulation, MHC-I is not internalized. | ||||||
| Mutagenesis | 72 | 1 | P → A: Complete loss of Nef-induced MHC-I down-modulation, MHC-I is not internalized; when associated with A-75. Ref.7 | ||||||
| Mutagenesis | 75 | 1 | P → A: Complete loss of Nef-induced MHC-I down-modulation, MHC-I is not internalized; when associated with A-72. Ref.7 | ||||||
| Sequence conflict | 29 | 1 | R → G in CAA26946. Ref.1 | ||||||
Sequences
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References
| [1] | "Polymorphism of the 3' open reading frame of the virus associated with the acquired immune deficiency syndrome, human T-lymphotropic virus type III." Ratner L., Starcich B.R., Josephs S.F., Hahn B.H., Reddy E.P., Livak K.J., Petteway S.R. Jr., Pearson M.L., Haseltine W.A., Arya S.K., Wong-staal F. Nucleic Acids Res. 13:8219-8229(1985) [PubMed: 2999715] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA]. |
| [2] | "Complete nucleotide sequences of functional clones of the AIDS virus." Ratner L., Fisher A., Jagodzinski L.L., Mitsuya H., Liou R.-S., Gallo R.C., Wong-Staal F. AIDS Res. Hum. Retroviruses 3:57-69(1987) [PubMed: 3040055] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA]. |
| [3] | Ratner L., Fisher A., Jagodzinski L.L., Mitsuya H., Liou R.-S., Gallo R.C., Wong-Staal F. Submitted (APR-1997) to the EMBL/GenBank/DDBJ databases Cited for: SEQUENCE REVISION. |
| [4] | "Nef induces CD4 endocytosis: requirement for a critical dileucine motif in the membrane-proximal CD4 cytoplasmic domain." Aiken C., Konner J., Landau N.R., Lenburg M.E., Trono D. Cell 76:853-864(1994) [PubMed: 8124721] [Abstract] Cited for: FUNCTION. Strain: Isolate HXB2/Clone R7. |
| [5] | "Nef-induced CD4 and major histocompatibility complex class I (MHC-I) down-regulation are governed by distinct determinants: N-terminal alpha helix and proline repeat of Nef selectively regulate MHC-I trafficking." Mangasarian A., Piguet V., Wang J.-K., Chen Y.-L., Trono D. J. Virol. 73:1964-1973(1999) [PubMed: 9971776] [Abstract] Cited for: FUNCTION. Strain: Isolate HXB2/Clone R7. |
| [6] | "HIV-1 Nef protein binds to the cellular protein PACS-1 to downregulate class I major histocompatibility complexes." Piguet V., Wan L., Borel C., Mangasarian A., Demaurex N., Thomas G., Trono D. Nat. Cell Biol. 2:163-167(2000) [PubMed: 10707087] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION. Strain: Isolate HXB2/Clone R7. |
| [7] | "HIV-1 Nef downregulates MHC-I by a PACS-1- and PI3K-regulated ARF6 endocytic pathway." Blagoveshchenskaya A.D., Thomas L., Feliciangeli S.F., Hung C.-H., Thomas G. Cell 111:853-866(2002) [PubMed: 12526811] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF MET-20; 63-GLU--GLU-65; PRO-72 AND PRO-75. Strain: Isolate HXB2D. |
| + | Additional computationally mapped references. |
Cross-references
Sequence databases | |
|---|---|
| X03187 Genomic RNA. Translation: CAA26946.1. K03455 Genomic RNA. Translation: AAB50263.1. AF033819 Genomic RNA. Translation: AAC82597.1. | |
3D structure databases | |
| SMR | P04601. Positions 1-56, 2-57, 55-122, 56-123. |
| ModBase | Search... |
Enzyme and pathway databases | |
| Pathway_Interaction_DB | hivnefpathway. HIV-1 Nef: Negative effector of Fas and TNF-alpha. |
| Reactome | REACT_6185. HIV Infection. |
Family and domain databases | |
| InterPro | IPR001558. HIV_Nef. [Graphical view] |
| Gene3D | G3DSA:3.30.62.10. HIV_Nef. 1 hit. |
| Pfam | PF00469. F-protein. 1 hit. [Graphical view] |
| ProtoNet | Search... |
Other Resources | |
| BindingDB | P04601. |
Entry information
| Entry name | NEF_HV1H2 | ||||||||
| Accession | Primary (citable) accession number: P04601 Secondary accession number(s): O09780, Q85587 | ||||||||
| Entry history |
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| Entry status | Reviewed (UniProtKB/Swiss-Prot) | ||||||||
| Annotation project | Virus (Virus annotation project) | ||||||||
