Q70627 (NEF_HV1LW) Reviewed, UniProtKB/Swiss-Prot
Last modified April 3, 2013. Version 94. History...
Names and origin
|Protein names||Recommended name:|
Cleaved into the following chain:
|Organism||Human immunodeficiency virus type 1 group M subtype B (isolate LW123) (HIV-1)|
|Taxonomic identifier||82834 [NCBI]|
|Taxonomic lineage||Viruses › Retro-transcribing viruses › Retroviridae › Orthoretrovirinae › Lentivirus › Primate lentivirus group ›|
|Virus host||Homo sapiens (Human) [TaxID: 9606]|
|Sequence length||206 AA.|
|Sequence processing||The displayed sequence is further processed into a mature form.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
Factor of infectivity and pathogenicity, required for optimal virus replication. Alters numerous pathways of T-lymphocytes 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. One of the earliest and most abundantly expressed viral proteins By similarity.
In 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) By similarity.
Bypasses 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 By similarity.
Plays 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. Interacts and decreases the half-life of p53, 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 Bad By similarity.
Extracellular Nef protein targets CD4+ T-lymphocytes for apoptosis by interacting with CXCR4 surface receptors By similarity.
Homodimer By similarity. 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 (via C-terminus). 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 latters. 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 TCR-zeta chain; this interaction up-regulates the Fas ligand (FasL) surface expression. Interacts with various cellular proteins including MAP3K5, beta-COP, HCK, and PTE1. Interacts with human GNB2L1/RACK1; this increases Nef phosphorylation by PKC By similarity.
Host cell membrane; Lipid-anchor; Cytoplasmic side By similarity. Host cytoplasm › host perinuclear region By similarity. Virion By similarity. Secreted By similarity. Note: Predominantly found in the paranuclear area, probably in the TGN. Correct localization requires PACS1. Also associates with the inner plasma membrane through its N-terminal domain. Nef stimulates its own export via the release of exosomes. Also incorporated in virions at a rate of about 10 molecules per virion, where it is cleaved By similarity.
The N-terminal 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 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.
The di-leucine internalization motif and a diacidic motif seem to be required for binding to AP-2 By similarity.
The acidic region may play a stabilizing role in the formation of a ternary complex between Nef, the MHC-I cytoplasmic domain, and AP1M1 By similarity.
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.
Phosphorylated on serine residues, probably by host PKC By similarity.
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).
Belongs to the lentivirus primate group Nef protein family.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Initiator methionine||1||1||Removed; by host By similarity|
|Chain||2 – 206||205||Protein Nef||PRO_0000038325|
|Chain||58 – 206||149||C-terminal core protein By similarity||PRO_0000038326|
|Region||2 – 57||56||N-terminal; associates with the host plasma membrane By similarity|
|Region||7 – 26||20||Necessary for MHC-I internalization By similarity|
|Region||62 – 65||4||Acidic; stabilizes the interaction of NEF/MHC-I with host AP1M1; necessary for MHC-I internalization and interaction with host PACS1 and PACS2 By similarity|
|Region||69 – 78||10||SH3-binding; interaction with Src family tyrosine kinases By similarity|
|Region||108 – 124||17||Mediates dimerization, Nef-PTE1 interaction, Nef-induced CD4 and MHC-I down-regulation and enhancement of infectivity By similarity|
|Region||148 – 180||33||Binding to ATP6V1H By similarity|
|Motif||72 – 75||4||PxxP; stabilizes the interaction of NEF/MHC-I with host AP1M1; necessary for MHC-I internalization By similarity|
|Motif||164 – 165||2||Di-leucine internalization motif; necessary for CD4 internalization By similarity|
|Motif||174 – 175||2||Diacidic; necessary for CD4 internalization By similarity|
|Site||20||1||Might play a role in AP-1 recruitment to the Nef-MHC-I complex By similarity|
|Site||57 – 58||2||Cleavage; by viral protease By similarity|
Amino acid modifications
|Lipidation||2||1||N-myristoyl glycine; by host By similarity|
Helix Strand Turn
|Helix||81 – 93||13|
|Helix||106 – 115||10|
|Turn||116 – 118||3|
|Beta strand||122 – 124||3|
|Beta strand||129 – 134||6|
|Beta strand||136 – 140||5|
|Beta strand||143 – 146||4|
|Beta strand||181 – 185||5|
|Helix||187 – 190||4|
|Helix||194 – 198||5|
|Helix||200 – 202||3|
|||"Viral variability and serum antibody response in a laboratory worker infected with HIV type 1 (HTLV type IIIB)."|
Reitz M.S. Jr., Hall L., Robert-Guroff M., Lautenberger J.A., Hahn B.M., Shaw G.M., Kong L.I., Weiss S.H., Waters D., Gallo R.C., Blattner W.
AIDS Res. Hum. Retroviruses 10:1143-1155(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA].
|||"Refined solution structure and backbone dynamics of HIV-1 Nef."|
Grzesiek S., Bax A., Hu J.S., Kaufman J., Palmer I., Stahl S.J., Tjandra N., Wingfield P.T.
Protein Sci. 6:1248-1263(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: STRUCTURE BY NMR OF 56-206.
|U12055 Genomic RNA. Translation: AAA76691.1.|
3D structure databases
|SMR||Q70627. Positions 2-205. |
Protocols and materials databases
Enzyme and pathway databases
|Reactome||REACT_116125. Disease. |
Family and domain databases
|Gene3D||126.96.36.199. 1 hit. |
|InterPro||IPR001558. HIV_Nef. |
|Pfam||PF00469. F-protein. 1 hit. |
|SUPFAM||SSF55671. HIV_Nef. 1 hit. |
|Accession||Primary (citable) accession number: Q70627|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Viral Protein Annotation Program|