Skip Header

 
Contribute Send feedback
Read comments (0) or add your own

Reviewed, UniProtKB/Swiss-Prot P04601 (NEF_HV1H2)

Last modified November 24, 2009. Version 85. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended 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
Name: nef
OrganismHuman immunodeficiency virus type 1 (isolate HXB2 group M subtype B) (HIV-1)
Taxonomic identifier11706 [NCBI]
Taxonomic lineageVirusesRetro-transcribing virusesRetroviridaeOrthoretrovirinaeLentivirusPrimate lentivirus group
Virus hostHomo sapiens (Human) [TaxID: 9606]

Protein attributes

Sequence length123 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence 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 cytoplasmhost 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.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed; by host By similarity
Chain2 – 123122Truncated Nef protein By similarity
PRO_0000038365
Chain58 – 12366C-terminal core protein By similarity
PRO_0000038366

Regions

Repeat69 – 7131
Repeat72 – 7432
Repeat75 – 7733
Repeat78 – 8034
Region2 – 5756Anchor By similarity
Region62 – 654Acidic cluster
Region69 – 80124 X 3 AA tandem repeats of P-X-X
Region108 – 12316Mediates dimerization, Nef-PTE1 interaction, Nef-induced CD4 and MHC-I down-modulation and enhancement of infectivity By similarity
Motif69 – 7810SH3-binding By similarity

Sites

Site201Involved in reducing surface MHC-I molecules by both impeding cell surface retrieval of MHC-I molecules and diverting them instead to the TGN
Site57 – 582Cleavage; by viral protease By similarity

Amino acid modifications

Lipidation21N-myristoyl glycine; by host By similarity

Experimental info

Mutagenesis201M → A: Complete loss of Nef-induced MHC-I down-modulation, MHC-I is internalized but not sequestred in TGN. Ref.7
Mutagenesis62 – 654EEEE → AAAA: Complete loss of Nef-induced MHC-I down-modulation, MHC-I is not internalized.
Mutagenesis721P → A: Complete loss of Nef-induced MHC-I down-modulation, MHC-I is not internalized; when associated with A-75. Ref.7
Mutagenesis751P → A: Complete loss of Nef-induced MHC-I down-modulation, MHC-I is not internalized; when associated with A-72. Ref.7
Sequence conflict291R → G in CAA26946. Ref.1

Sequences

Sequence LengthMass (Da)Tools
P04601-1 [UniParc].

Last modified January 23, 2007. Version 4.
Checksum: B5007753CCD244CF

FASTA12313,692
        10         20         30         40         50         60 
MGGKWSKSSV IGWPTVRERM RRAEPAADRV GAASRDLEKH GAITSSNTAA TNAACAWLEA 

        70         80         90        100        110        120 
QEEEEVGFPV TPQVPLRPMT YKAAVDLSHF LKEKGGLEGL IHSQRRQDIL DLWIYHTQGY 


FPD 

« Hide

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

SMRP04601. Positions 1-56, 2-57, 55-122, 56-123.
ModBaseSearch...

Enzyme and pathway databases

Pathway_Interaction_DBhivnefpathway. HIV-1 Nef: Negative effector of Fas and TNF-alpha.
ReactomeREACT_6185. HIV Infection.

Family and domain databases

InterProIPR001558. HIV_Nef.
[Graphical view]
Gene3DG3DSA:3.30.62.10. HIV_Nef. 1 hit.
PfamPF00469. F-protein. 1 hit.
[Graphical view]
ProtoNetSearch...

Other Resources

BindingDBP04601.

Entry information

Entry nameNEF_HV1H2
AccessionPrimary (citable) accession number: P04601
Secondary accession number(s): O09780, Q85587
Entry history
Integrated into UniProtKB/Swiss-Prot: August 13, 1987
Last sequence update: January 23, 2007
Last modified: November 24, 2009
This is version 85 of the entry and version 4 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation projectVirus (Virus annotation project)

Relevant documents

SIMILARITY comments

Index of protein domains and families

Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents