Q70627 (NEF_HV1LW) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Protein Nef

Alternative name(s):
3'ORF
Negative factor
Short name=F-protein

Cleaved into the following chain:

1. C-terminal core protein

Gene names

Name:

nef

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 › Human immunodeficiency virus 1 › HIV-1 unknown group

Virus host

Homo sapiens (Human) [TaxID: 9606]

Protein attributes

Sequence length	206 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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.
Subunit structure	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.
Subcellular location	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.
Domain	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.
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. Phosphorylated on serine residues, probably by host PKC By similarity.
Miscellaneous	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.

Ontologies

Keywords
Biological process	Apoptosis Host-virus interaction Inhibition of host MHC class I molecule presentation by virus Inhibition of host MHC class II molecule presentation by virus Inhibition of host adaptive immune response by virus Inhibition of host autophagy by virus Viral immunoevasion Virulence
Cellular component	Host cell membrane Host cytoplasm Host membrane Membrane Secreted Virion
Developmental stage	Early protein
Disease	AIDS
Domain	SH3-binding
PTM	Lipoprotein Myristate Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological_process	apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW negative regulation by symbiont of host T-cell mediated immune response Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of CD4 biosynthetic process Inferred from sequence or structural similarity. Source: UniProtKB pathogenesis Inferred from sequence or structural similarity. Source: UniProtKB regulation of calcium-mediated signaling Inferred from sequence or structural similarity. Source: UniProtKB suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Inferred from sequence or structural similarity. Source: UniProtKB suppression by virus of host antigen processing and presentation of peptide antigen via MHC class II Inferred from electronic annotation. Source: UniProtKB-KW suppression by virus of host autophagy Inferred from electronic annotation. Source: UniProtKB-KW viral infectious cycle Inferred from sequence or structural similarity. Source: UniProtKB
Cellular_component	cytosol Traceable author statement. Source: Reactome host cell perinuclear region of cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell host cell plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell membrane Inferred from electronic annotation. Source: UniProtKB-KW virion Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATPase binding Inferred from sequence or structural similarity. Source: UniProtKB CD4 receptor binding Inferred from sequence or structural similarity. Source: UniProtKB GTP binding Inferred from electronic annotation. Source: InterPro MHC class I protein binding Inferred from sequence or structural similarity. Source: UniProtKB SH3 domain binding Inferred from sequence or structural similarity. Source: UniProtKB calmodulin binding Inferred from sequence or structural similarity. Source: UniProtKB protein kinase binding Inferred from sequence or structural similarity. Source: UniProtKB thioesterase binding Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

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

Regions

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

Sites

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

Secondary structure

1

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206

Helix Strand Turn

Details...

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

Sequences

	Sequence		Length	Mass (Da)
	Q70627 [UniParc]. Last modified January 23, 2007. Version 3. Checksum: ED81F68F6B61278E	FASTA	206	23,414
	10 20 30 40 50 60 MGGKWSKSSV IGWPTVRERM RRAEPAADGV GAASQDLEKH GAITSSNTAA TNADCAWLEA 70 80 90 100 110 120 QEEEEVGFPV TPQVPLRPMT YKAAVDLSHF LKEKGGLEGL IHSQRRQDIL DLWIYHTQGY 130 140 150 160 170 180 FPDWQNYTPG PGIRYPLTFG WCYKLVPVEP EKLEEANKGE NTSLLHPVSL HGMDDPEREV 190 200 LEWRFDSRLA FHHVARELHP EYFKNC

References

[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] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA].
[2]	"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.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U12055 Genomic RNA. Translation: AAA76691.1.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2NEF	NMR	-	A	56-205	[»]

ProteinModelPortal

Q70627.

SMR

Q70627. Positions 2-205.

ModBase

Search...

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Enzyme and pathway databases

Reactome

REACT_116125. Disease.

Family and domain databases

Gene3D

3.30.62.10. 1 hit.

InterPro

IPR001558. HIV_Nef.
[Graphical view]

Pfam

PF00469. F-protein. 1 hit.
[Graphical view]

SUPFAM

SSF55671. HIV_Nef. 1 hit.

ProtoNet

Search...

Other

EvolutionaryTrace

Q70627.

Entry information

Entry name

NEF_HV1LW

Accession

Primary (citable) accession number: Q70627

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1998
Last sequence update:	January 23, 2007
Last modified:	April 3, 2013
This is version 94 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Viral Protein Annotation Program