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Protein

Protein Nef

Gene

nef

Organism
Human immunodeficiency virus type 1 group M subtype B (isolate BRU/LAI) (HIV-1)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Factor of infectivity and pathogenicity, required for optimal virus replication (PubMed:8151761). Alters numerous pathways of T-lymphocytes function and down-regulates immunity surface molecules in order to evade host defense and increase viral infectivity (PubMed:25585010). Alters the functionality of other immunity cells, like dendritic cells, monocytes/macrophages and NK cells (PubMed:25585010).2 Publications
In infected CD4+ T-lymphocytes, down-regulates the surface MHC-I, mature MHC-II, CD4, CD28, CCR5 and CXCR4 molecules (PubMed:10684310, PubMed:11285224) (PubMed:14617802) (PubMed:15854903, PubMed:16928758). 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 (By similarity). 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 (PubMed:18005690). 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). Down-regulates host SERINC3 and SERINC5 thereby excluding these proteins from the viral particles. Virion infectivity is drastically higher when SERINC3 or SERINC5 are excluded from the viral envelope, because these host antiviral proteins impare the membrane fusion event necessary for subsequent virion penetration (PubMed:26416734) (PubMed:26416733).By similarity8 Publications
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) (By similarity). Increasing surface FasL molecules and decreasing surface MHC-I molecules on infected CD4+ cells send attacking cytotoxic CD8+ T-lymphocytes into apoptosis (PubMed:11298454).By similarity1 Publication
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/ASK1 (PubMed:11298454). Decreases the half-life of TP53, protecting the infected cell against p53-mediated apoptosis (PubMed:11861836). 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 similarity2 Publications
Extracellular Nef protein targets CD4+ T-lymphocytes for apoptosis by interacting with CXCR4 surface receptors (PubMed:14990729).1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei20Might play a role in AP-1 recruitment to the Nef-MHC-I complexBy similarity1

GO - Molecular functioni

  • ATPase binding Source: UniProtKB
  • calmodulin binding Source: UniProtKB
  • CD4 receptor binding Source: UniProtKB
  • GTP binding Source: InterPro
  • MHC class I protein binding Source: UniProtKB
  • protein kinase binding Source: UniProtKB
  • receptor binding Source: UniProtKB
  • SH3 domain binding Source: UniProtKB
  • thioesterase binding Source: UniProtKB

GO - Biological processi

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):
3'ORF
Negative factor
Short name:
F-protein
Cleaved into the following chain:
Gene namesi
Name:nef
OrganismiHuman immunodeficiency virus type 1 group M subtype B (isolate BRU/LAI) (HIV-1)
Taxonomic identifieri11686 [NCBI]
Taxonomic lineageiVirusesRetro-transcribing virusesRetroviridaeOrthoretrovirinaeLentivirusPrimate lentivirus group
Virus hostiHomo sapiens (Human) [TaxID: 9606]
Proteomesi
  • UP000007692 Componenti: Genome

Subcellular locationi

  • Host cell membrane 1 Publication; Lipid-anchor 1 Publication; Cytoplasmic side 1 Publication
  • Virion 2 Publications
  • Secreted By similarity
  • Host Golgi apparatus membrane 1 Publication

  • Note: TGN localization requires PACS1. Associates with the inner plasma membrane through its N-terminal domain. Nef stimulates its own export via the release of exosomes. Incorporated in virions at a rate of about 10 molecules per virion, where it is cleaved.By similarity3 Publications

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Host cell membrane, Host Golgi apparatus, Host membrane, Membrane, Secreted, Virion

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi2 – 3GG → AA: 70% loss of infectivity. 1 Publication2
Mutagenesisi20M → A: Amost complete loss of Nef-induced MHC-I down-regulation. 1 Publication1
Mutagenesisi20M → R: Amost complete loss of Nef-induced MHC-I down-regulation. 1 Publication1
Mutagenesisi71T → R: Increases infectivity by a factor of three. 1 Publication1
Mutagenesisi72P → A: Complete loss of binding to HCK SH3 domain and altered viral growth; when associated with P-76. No effect on Nef-induced CD4 down-regulation. 1 Publication1
Mutagenesisi75P → A: Complete loss of binding to HCK SH3 domain and altered viral growth; when associated with P-73. No effect on Nef-induced CD4 down-regulation. 1 Publication1
Mutagenesisi147P → A: Complete loss of binding to HCK SH3 domain and altered viral growth. No effect on Nef-induced CD4 down-modulation. 1 Publication1
Mutagenesisi150P → A: No effect. 1 Publication1
Mutagenesisi164 – 165LL → AA: Loss of interaction with AP-2 complex. 1 Publication2
Mutagenesisi174 – 175DD → AA: Loss of interaction with AP-2 complex. 1 Publication2

Keywords - Diseasei

AIDS

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemoved; by host
ChainiPRO_00000383352 – 206Protein NefAdd BLAST205
ChainiPRO_000003833658 – 206C-terminal core proteinAdd BLAST149

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Lipidationi2N-myristoyl glycine; by host1 Publication1
Modified residuei6Phosphoserine; by hostBy similarity1

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.2 Publications
Myristoylated.1 Publication
Phosphorylated on serine residues, probably by host PKCdelta and theta.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei57 – 58Cleavage; by viral protease1 Publication2

Keywords - PTMi

Lipoprotein, Myristate, Phosphoprotein

Expressioni

Keywords - Developmental stagei

Early protein

Interactioni

Subunit structurei

Monomer; cytosolic form (By similarity). Homodimer; membrane bound form (PubMed:19781555). Interacts with Nef associated p21-activated kinase (PAK2); this interaction activates PAK2 (PubMed:11070003). Associates with the Nef-MHC-I-AP1 complex; this complex is required for MHC-I internalization (By similarity). Interacts (via C-terminus) with host PI3-kinase (via C-terminus) (By similarity). Interacts with host PACS1; this interaction seems to be weak (By similarity). Interacts with host PACS2 (By similarity). Interacts with host LCK and MAPK3; these interactions inhibit the kinase activity of the latters (PubMed:8794306). Interacts with host ATP6V1H; this interaction may play a role in CD4 endocytosis (By similarity). Associates with the CD4-Nef-AP2 complex; this complex is required for CD4 internalization (PubMed:18032517). Interacts with host AP2 subunit alpha and AP2 subunit sigma2 (By similarity). Interacts with TCR-zeta chain; this interaction up-regulates the Fas ligand (FasL) surface expression (By similarity). Interacts with host HCK, LYN, and SRC; these interactions activate the Src family kinases (By similarity). Interacts with MAP3K5; this interaction inhibits the Fas and TNFR-mediated death signals (PubMed:11298454). Interacts with beta-COP and PTE1. Interacts with human RACK1; this increases Nef phosphorylation by PKC (By similarity). Interacts with TP53; this interaction decreases the half-life of TP53, protecting the infected cell against p53-mediated apoptosis (PubMed:11861836).By similarity6 Publications

GO - Molecular functioni

  • ATPase binding Source: UniProtKB
  • calmodulin binding Source: UniProtKB
  • CD4 receptor binding Source: UniProtKB
  • MHC class I protein binding Source: UniProtKB
  • protein kinase binding Source: UniProtKB
  • receptor binding Source: UniProtKB
  • SH3 domain binding Source: UniProtKB
  • thioesterase binding Source: UniProtKB

Protein-protein interaction databases

DIPiDIP-29968N.

Chemistry databases

BindingDBiP03406.

Structurei

Secondary structure

1206
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi81 – 93Combined sources13
Turni97 – 99Combined sources3
Helixi104 – 118Combined sources15
Beta strandi130 – 132Combined sources3
Beta strandi136 – 138Combined sources3
Beta strandi143 – 147Combined sources5
Beta strandi181 – 185Combined sources5
Helixi187 – 190Combined sources4
Helixi194 – 198Combined sources5
Helixi200 – 202Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1AVVX-ray3.00A58-206[»]
1AVZX-ray3.00A/B58-206[»]
1EFNX-ray2.50B/D54-205[»]
4D8DX-ray2.52B/D58-204[»]
DisProtiDP00048.
ProteinModelPortaliP03406.
SMRiP03406.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP03406.

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni62 – 65Acidic; interacts with host PACS1 and PACS2; stabilizes the interaction of NEF/MHC-I with host AP1M1; necessary for MHC-I internalizationBy similarity4
Regioni69 – 78SH3-binding; interaction with Src family tyrosine kinases2 Publications10
Regioni108 – 124Mediates dimerization, Nef-PTE1 interaction, Nef-induced CD4 and MHC-I down-regulation and enhancement of infectivity1 PublicationAdd BLAST17
Regioni148 – 180Binding to ATP6V1HBy similarityAdd BLAST33

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi72 – 75PxxP; stabilizes the interaction of NEF/MHC-I with host AP1M1; necessary for MHC-I internalizationBy similarity4
Motifi164 – 165Dileucine internalization motif; necessary for CD4 internalizationBy similarity2
Motifi174 – 175Diacidic; necessary for CD4 internalization1 Publication2

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi62 – 65Poly-Glu4

Domaini

The N-terminal domain is composed of the N-myristoyl glycine and of a cluster of positively charged amino acids (PubMed:8151761). It is required for inner plasma membrane targeting of Nef and virion incorporation, and thereby for infectivity (PubMed:8151761). This domain is also involved in binding to p53 (PubMed:11861836).2 Publications
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.2 Publications
The dileucine internalization motif and a diacidic motif seem to be required for binding to AP-2.1 Publication
The acidic region binds to the sorting protein PACS-2, which targets Nef to the paranuclear region, enabling the PxxP motif to direct assembly of an SFK/ZAP-70/PI3K complex that accelerates endocytosis of cell-surface MHC-I.By similarity

Sequence similaritiesi

Keywords - Domaini

SH3-binding

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.

Sequencei

Sequence statusi: Complete.

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

P03406-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MGGKWSKSSV VGWPTVRERM RRAEPAADGV GAASRDLEKH GAITSSNTAA
60 70 80 90 100
TNAACAWLEA QEEEEVGFPV TPQVPLRPMT YKAAVDLSHF LKEKGGLEGL
110 120 130 140 150
IHSQRRQDIL DLWIYHTQGY FPDWQNYTPG PGVRYPLTFG WCYKLVPVEP
160 170 180 190 200
DKVEEANKGE NTSLLHPVSL HGMDDPEREV LEWRFDSRLA FHHVARELHP

EYFKNC
Length:206
Mass (Da):23,342
Last modified:January 23, 2007 - v3
Checksum:i77453FC80B6004F2
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural varianti11V → I in strain: Clone pNL4-3. 1
Natural varianti15T → A in strain: Clone pNL4-3. 1
Natural varianti33A → V in strain: Clone pNL4-3. 1
Natural varianti51T → N in strain: Clone pNL4-3. 1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
K02013 Genomic RNA. Translation: AAB59752.1.
M19921 Genomic RNA. Translation: AAA44993.1.
A04321 Unassigned RNA. Translation: CAA00353.1.
PIRiA04008. ASLJFV.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
K02013 Genomic RNA. Translation: AAB59752.1.
M19921 Genomic RNA. Translation: AAA44993.1.
A04321 Unassigned RNA. Translation: CAA00353.1.
PIRiA04008. ASLJFV.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1AVVX-ray3.00A58-206[»]
1AVZX-ray3.00A/B58-206[»]
1EFNX-ray2.50B/D54-205[»]
4D8DX-ray2.52B/D58-204[»]
DisProtiDP00048.
ProteinModelPortaliP03406.
SMRiP03406.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

DIPiDIP-29968N.

Chemistry databases

BindingDBiP03406.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Miscellaneous databases

EvolutionaryTraceiP03406.

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.
ProtoNetiSearch...

Entry informationi

Entry nameiNEF_HV1BR
AccessioniPrimary (citable) accession number: P03406
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 21, 1986
Last sequence update: January 23, 2007
Last modified: November 30, 2016
This is version 145 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programViral Protein Annotation Program

Miscellaneousi

Miscellaneous

The infectious clone pNL4-3 is a chimeric provirus that consists of DNA from HIV isolates NY5 (5' half) and BRU (3' half).
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

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

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

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 one 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.