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Q70627 - NEF_HV1LW


Protein Nef



Human immunodeficiency virus type 1 group M subtype B (isolate LW123) (HIV-1)
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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      Entry version 102 (01 Oct 2014)
      Sequence version 3 (23 Jan 2007)
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    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.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.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.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.By similarity
    Extracellular Nef protein targets CD4+ T-lymphocytes for apoptosis by interacting with CXCR4 surface receptors.By similarity


    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sitei20 – 201Might play a role in AP-1 recruitment to the Nef-MHC-I complexBy similarity
    Sitei57 – 582Cleavage; by viral proteaseBy similarity

    GO - Molecular functioni

    1. ATPase binding Source: UniProtKB
    2. calmodulin binding Source: UniProtKB
    3. CD4 receptor binding Source: UniProtKB
    4. GTP binding Source: InterPro
    5. MHC class I protein binding Source: UniProtKB
    6. protein kinase binding Source: UniProtKB
    7. receptor binding Source: UniProtKB
    8. SH3 domain binding Source: UniProtKB
    9. thioesterase binding Source: UniProtKB

    GO - Biological processi

    1. apoptotic process Source: UniProtKB-KW
    2. negative regulation by symbiont of host T-cell mediated immune response Source: UniProtKB
    3. negative regulation of CD4 biosynthetic process Source: UniProtKB
    4. pathogenesis Source: UniProtKB
    5. regulation of calcium-mediated signaling Source: UniProtKB
    6. suppression by virus of host adaptive immune response Source: UniProtKB-KW
    7. suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Source: UniProtKB
    8. suppression by virus of host antigen processing and presentation of peptide antigen via MHC class II Source: UniProtKB-KW
    9. suppression by virus of host autophagy Source: UniProtKB-KW
    10. viral life cycle Source: UniProtKB

    Keywords - Biological processi

    Apoptosis, Host-virus interaction, Inhibition of host adaptive immune response by virus, Inhibition of host autophagy by virus, Inhibition of host MHC class I molecule presentation by virus, Inhibition of host MHC class II molecule presentation by virus, Viral immunoevasion, Virulence

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Protein Nef
    Alternative name(s):
    Negative factor
    Short name:
    Cleaved into the following chain:
    Gene namesi
    OrganismiHuman immunodeficiency virus type 1 group M subtype B (isolate LW123) (HIV-1)
    Taxonomic identifieri82834 [NCBI]
    Taxonomic lineageiVirusesRetro-transcribing virusesRetroviridaeOrthoretrovirinaeLentivirusPrimate lentivirus group
    Virus hostiHomo sapiens (Human) [TaxID: 9606]

    Subcellular locationi

    Host cell membrane By similarity; Lipid-anchor By similarity; Cytoplasmic side By similarity. Host cytoplasmhost 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.By similarity

    GO - Cellular componenti

    1. host cell perinuclear region of cytoplasm Source: UniProtKB-SubCell
    2. host cell plasma membrane Source: UniProtKB-SubCell
    3. membrane Source: UniProtKB-KW
    4. virion Source: UniProtKB-SubCell

    Keywords - Cellular componenti

    Host cell membrane, Host cytoplasm, Host membrane, Membrane, Secreted, Virion

    Pathology & Biotechi

    Keywords - Diseasei


    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Initiator methioninei1 – 11Removed; by hostBy similarity
    Chaini2 – 206205Protein NefPRO_0000038325Add
    Chaini58 – 206149C-terminal core proteinBy similarityPRO_0000038326Add

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Lipidationi2 – 21N-myristoyl glycine; by hostBy similarity

    Post-translational modificationi

    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.By similarity
    Phosphorylated on serine residues, probably by host PKC.By similarity

    Keywords - PTMi

    Lipoprotein, Myristate, Phosphoprotein


    Keywords - Developmental stagei

    Early protein


    Subunit structurei

    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.By similarity


    Secondary structure

    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Helixi81 – 9313
    Helixi106 – 11510
    Turni116 – 1183
    Beta strandi122 – 1243
    Beta strandi129 – 1346
    Beta strandi136 – 1405
    Beta strandi143 – 1464
    Beta strandi181 – 1855
    Helixi187 – 1904
    Helixi194 – 1985
    Helixi200 – 2023

    3D structure databases

    Select the link destinations:
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    SMRiQ70627. Positions 2-205.

    Miscellaneous databases


    Family & Domainsi


    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni2 – 5756N-terminal; associates with the host plasma membraneBy similarityAdd
    Regioni7 – 2620Necessary for MHC-I internalizationBy similarityAdd
    Regioni62 – 654Acidic; stabilizes the interaction of NEF/MHC-I with host AP1M1; necessary for MHC-I internalization and interaction with host PACS1 and PACS2By similarity
    Regioni69 – 7810SH3-binding; interaction with Src family tyrosine kinasesBy similarity
    Regioni108 – 12417Mediates dimerization, Nef-PTE1 interaction, Nef-induced CD4 and MHC-I down-regulation and enhancement of infectivityBy similarityAdd
    Regioni148 – 18033Binding to ATP6V1HBy similarityAdd


    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Motifi72 – 754PxxP; stabilizes the interaction of NEF/MHC-I with host AP1M1; necessary for MHC-I internalizationBy similarity
    Motifi164 – 1652Di-leucine internalization motif; necessary for CD4 internalizationBy similarity
    Motifi174 – 1752Diacidic; necessary for CD4 internalizationBy 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.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.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

    Sequence similaritiesi

    Keywords - Domaini


    Family and domain databases

    Gene3Di3.30.62.10. 1 hit.
    4.10.890.10. 1 hit.
    InterProiIPR027480. HIV-1_Nef_anchor.
    IPR027481. HIV-1_Nef_core.
    IPR001558. HIV_Nef.
    [Graphical view]
    PfamiPF00469. F-protein. 1 hit.
    [Graphical view]
    SUPFAMiSSF55671. SSF55671. 1 hit.


    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    Q70627-1 [UniParc]FASTAAdd to Basket

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    EYFKNC 206
    Mass (Da):23,414
    Last modified:January 23, 2007 - v3

    Sequence databases

    Select the link destinations:
    Links Updated
    U12055 Genomic RNA. Translation: AAA76691.1.


    Sequence databases

    Select the link destinations:
    Links Updated
    U12055 Genomic RNA. Translation: AAA76691.1 .

    3D structure databases

    Select the link destinations:
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    2NEF NMR - A 56-205 [» ]
    ProteinModelPortali Q70627.
    SMRi Q70627. Positions 2-205.
    ModBasei Search...
    MobiDBi Search...

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Miscellaneous databases

    EvolutionaryTracei Q70627.

    Family and domain databases

    Gene3Di 1 hit.
    4.10.890.10. 1 hit.
    InterProi IPR027480. HIV-1_Nef_anchor.
    IPR027481. HIV-1_Nef_core.
    IPR001558. HIV_Nef.
    [Graphical view ]
    Pfami PF00469. F-protein. 1 hit.
    [Graphical view ]
    SUPFAMi SSF55671. SSF55671. 1 hit.
    ProtoNeti Search...


    1. "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]
    2. Cited for: STRUCTURE BY NMR OF 56-206.

    Entry informationi

    Entry nameiNEF_HV1LW
    AccessioniPrimary (citable) accession number: Q70627
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: July 15, 1998
    Last sequence update: January 23, 2007
    Last modified: October 1, 2014
    This is version 102 of the entry and version 3 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programViral Protein Annotation Program



    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).

    Keywords - Technical termi



    1. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    2. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3