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Q70627 - NEF_HV1LW

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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


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
Complete GO annotation...

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
Complete GO annotation...

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 – 9313Combined sources
Helixi106 – 11510Combined sources
Turni116 – 1183Combined sources
Beta strandi122 – 1243Combined sources
Beta strandi129 – 1346Combined sources
Beta strandi136 – 1405Combined sources
Beta strandi143 – 1464Combined sources
Beta strandi181 – 1855Combined sources
Helixi187 – 1904Combined sources
Helixi194 – 1985Combined sources
Helixi200 – 2023Combined sources

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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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: January 7, 2015
This is version 105 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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.