| IED ID | IndEnz0002004423 |
| Enzyme Type ID | protease004423 |
| Protein Name |
Protein Nef 3'ORF Negative factor F-protein Cleaved into: C-terminal core protein |
| Gene Name | nef |
| Organism | Human immunodeficiency virus type 1 group M subtype D (isolate NDK) (HIV-1) |
| Taxonomic Lineage | Viruses Riboviria Pararnavirae Artverviricota Revtraviricetes Ortervirales Retroviridae Orthoretrovirinae Lentivirus Human immunodeficiency virus 1 HIV-1 unknown group Human immunodeficiency virus type 1 group M subtype D (isolate NDK) (HIV-1) |
| Enzyme Sequence | MGGKWSKSSLVGWPAIRERIRKTDPAADGVGAVSRDLEKHGAITSSNTASTNDTCAWLEAQEESEEVGFPVRPQVPLRPMTYKEAVDLSHFLKEKGGLEGLIWSKKRQEILDLWVYNTQGIFPDWQNYTPGPGIRYPLTFGWCFQLVPVDPQEVEEATEREDNCLLHPMCQQGMEDPERQVLMWRFNSRLALEHKARELHPEFYKDC |
| Enzyme Length | 207 |
| Uniprot Accession Number | P18801 |
| Absorption | |
| Active Site | |
| Activity Regulation | |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | |
| DNA Binding | |
| EC Number | |
| Enzyme Function | FUNCTION: Factor of infectivity and pathogenicity, required for optimal virus replication. Alters numerous pathways of T-lymphocyte 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. {ECO:0000255|HAMAP-Rule:MF_04078}.; FUNCTION: 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). 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 impair the membrane fusion event necessary for subsequent virion penetration. {ECO:0000255|HAMAP-Rule:MF_04078}.; FUNCTION: 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. {ECO:0000255|HAMAP-Rule:MF_04078}.; FUNCTION: 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. Decreases the half-life of TP53, 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 host BAD. {ECO:0000255|HAMAP-Rule:MF_04078}.; FUNCTION: Extracellular Nef protein targets CD4(+) T-lymphocytes for apoptosis by interacting with CXCR4 surface receptors. {ECO:0000255|HAMAP-Rule:MF_04078}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Chain (2); Initiator methionine (1); Lipidation (1); Modified residue (1); Motif (3); Region (4); Site (1) |
| Keywords | AIDS;Apoptosis;Early protein;Host Golgi apparatus;Host cell membrane;Host membrane;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;Lipoprotein;Membrane;Myristate;Phosphoprotein;SH3-binding;Secreted;Viral immunoevasion;Virion;Virulence |
| Interact With | |
| Induction | INDUCTION: Expressed early in the viral replication cycle. {ECO:0000255|HAMAP-Rule:MF_04078}. |
| Subcellular Location | SUBCELLULAR LOCATION: Host cell membrane {ECO:0000255|HAMAP-Rule:MF_04078}; Lipid-anchor {ECO:0000255|HAMAP-Rule:MF_04078}; Cytoplasmic side {ECO:0000255|HAMAP-Rule:MF_04078}. Virion {ECO:0000255|HAMAP-Rule:MF_04078}. Secreted {ECO:0000255|HAMAP-Rule:MF_04078}. Host Golgi apparatus membrane {ECO:0000255|HAMAP-Rule:MF_04078}. 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. {ECO:0000255|HAMAP-Rule:MF_04078}. |
| Modified Residue | MOD_RES 6; /note=Phosphoserine; by host; /evidence=ECO:0000255|HAMAP-Rule:MF_04078 |
| Post Translational Modification | PTM: 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. {ECO:0000255|HAMAP-Rule:MF_04078}.; PTM: Myristoylated. {ECO:0000255|HAMAP-Rule:MF_04078}.; PTM: Phosphorylated on serine residues, probably by host PKCdelta and theta. {ECO:0000255|HAMAP-Rule:MF_04078}. |
| Signal Peptide | |
| Structure 3D | |
| Cross Reference PDB | - |
| Mapped Pubmed ID | - |
| Motif | MOTIF 73..76; /note=PxxP; stabilizes the interaction of NEF/MHC-I with host AP1M1; necessary for MHC-I internalization; /evidence=ECO:0000255|HAMAP-Rule:MF_04078; MOTIF 165..166; /note=Dileucine internalization motif; necessary for CD4 internalization; /evidence=ECO:0000255|HAMAP-Rule:MF_04078; MOTIF 175..176; /note=Diacidic; necessary for CD4 internalization; /evidence=ECO:0000255|HAMAP-Rule:MF_04078 |
| Gene Encoded By | |
| Mass | 23,748 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda |