4u5w

Structural highlights

Function

NEF_HV1A2 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).^{[1] [2] [3] [4] [5] [6]} 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).^{[7] [8] [9] [10] [11] [12]} 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).^{[13] [14] [15] [16] [17] [18]} 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).^{[19] [20] [21] [22] [23] [24]} Extracellular Nef protein targets CD4(+) T-lymphocytes for apoptosis by interacting with CXCR4 surface receptors (By similarity).^{[25] [26] [27] [28] [29] [30]}

See Also

• Protein Nef 3D structures
• Tyrosine kinase 3D structures

References

1. ↑ Briggs SD, Sharkey M, Stevenson M, Smithgall TE. SH3-mediated Hck tyrosine kinase activation and fibroblast transformation by the Nef protein of HIV-1. J Biol Chem. 1997 Jul 18;272(29):17899-902. PMID:9218412
2. ↑ Xu XN, Laffert B, Screaton GR, Kraft M, Wolf D, Kolanus W, Mongkolsapay J, McMichael AJ, Baur AS. Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain. J Exp Med. 1999 May 3;189(9):1489-96. PMID:10224289
3. ↑ Kim YH, Chang SH, Kwon JH, Rhee SS. HIV-1 Nef plays an essential role in two independent processes in CD4 down-regulation: dissociation of the CD4-p56(lck) complex and targeting of CD4 to lysosomes. Virology. 1999 Apr 25;257(1):208-19. PMID:10208934 doi:S0042-6822(99)99642-3
4. ↑ Arora VK, Molina RP, Foster JL, Blakemore JL, Chernoff J, Fredericksen BL, Garcia JV. Lentivirus Nef specifically activates Pak2. J Virol. 2000 Dec;74(23):11081-7. PMID:11070003
5. ↑ Simmons A, Aluvihare V, McMichael A. Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators. Immunity. 2001 Jun;14(6):763-77. PMID:11420046
6. ↑ Wolf D, Witte V, Laffert B, Blume K, Stromer E, Trapp S, d'Aloja P, Schurmann A, Baur AS. HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals. Nat Med. 2001 Nov;7(11):1217-24. PMID:11689886 doi:10.1038/nm1101-1217
7. ↑ Briggs SD, Sharkey M, Stevenson M, Smithgall TE. SH3-mediated Hck tyrosine kinase activation and fibroblast transformation by the Nef protein of HIV-1. J Biol Chem. 1997 Jul 18;272(29):17899-902. PMID:9218412
8. ↑ Xu XN, Laffert B, Screaton GR, Kraft M, Wolf D, Kolanus W, Mongkolsapay J, McMichael AJ, Baur AS. Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain. J Exp Med. 1999 May 3;189(9):1489-96. PMID:10224289
9. ↑ Kim YH, Chang SH, Kwon JH, Rhee SS. HIV-1 Nef plays an essential role in two independent processes in CD4 down-regulation: dissociation of the CD4-p56(lck) complex and targeting of CD4 to lysosomes. Virology. 1999 Apr 25;257(1):208-19. PMID:10208934 doi:S0042-6822(99)99642-3
10. ↑ Arora VK, Molina RP, Foster JL, Blakemore JL, Chernoff J, Fredericksen BL, Garcia JV. Lentivirus Nef specifically activates Pak2. J Virol. 2000 Dec;74(23):11081-7. PMID:11070003
11. ↑ Simmons A, Aluvihare V, McMichael A. Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators. Immunity. 2001 Jun;14(6):763-77. PMID:11420046
12. ↑ Wolf D, Witte V, Laffert B, Blume K, Stromer E, Trapp S, d'Aloja P, Schurmann A, Baur AS. HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals. Nat Med. 2001 Nov;7(11):1217-24. PMID:11689886 doi:10.1038/nm1101-1217
13. ↑ Briggs SD, Sharkey M, Stevenson M, Smithgall TE. SH3-mediated Hck tyrosine kinase activation and fibroblast transformation by the Nef protein of HIV-1. J Biol Chem. 1997 Jul 18;272(29):17899-902. PMID:9218412
14. ↑ Xu XN, Laffert B, Screaton GR, Kraft M, Wolf D, Kolanus W, Mongkolsapay J, McMichael AJ, Baur AS. Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain. J Exp Med. 1999 May 3;189(9):1489-96. PMID:10224289
15. ↑ Kim YH, Chang SH, Kwon JH, Rhee SS. HIV-1 Nef plays an essential role in two independent processes in CD4 down-regulation: dissociation of the CD4-p56(lck) complex and targeting of CD4 to lysosomes. Virology. 1999 Apr 25;257(1):208-19. PMID:10208934 doi:S0042-6822(99)99642-3
16. ↑ Arora VK, Molina RP, Foster JL, Blakemore JL, Chernoff J, Fredericksen BL, Garcia JV. Lentivirus Nef specifically activates Pak2. J Virol. 2000 Dec;74(23):11081-7. PMID:11070003
17. ↑ Simmons A, Aluvihare V, McMichael A. Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators. Immunity. 2001 Jun;14(6):763-77. PMID:11420046
18. ↑ Wolf D, Witte V, Laffert B, Blume K, Stromer E, Trapp S, d'Aloja P, Schurmann A, Baur AS. HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals. Nat Med. 2001 Nov;7(11):1217-24. PMID:11689886 doi:10.1038/nm1101-1217
19. ↑ Briggs SD, Sharkey M, Stevenson M, Smithgall TE. SH3-mediated Hck tyrosine kinase activation and fibroblast transformation by the Nef protein of HIV-1. J Biol Chem. 1997 Jul 18;272(29):17899-902. PMID:9218412
20. ↑ Xu XN, Laffert B, Screaton GR, Kraft M, Wolf D, Kolanus W, Mongkolsapay J, McMichael AJ, Baur AS. Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain. J Exp Med. 1999 May 3;189(9):1489-96. PMID:10224289
21. ↑ Kim YH, Chang SH, Kwon JH, Rhee SS. HIV-1 Nef plays an essential role in two independent processes in CD4 down-regulation: dissociation of the CD4-p56(lck) complex and targeting of CD4 to lysosomes. Virology. 1999 Apr 25;257(1):208-19. PMID:10208934 doi:S0042-6822(99)99642-3
22. ↑ Arora VK, Molina RP, Foster JL, Blakemore JL, Chernoff J, Fredericksen BL, Garcia JV. Lentivirus Nef specifically activates Pak2. J Virol. 2000 Dec;74(23):11081-7. PMID:11070003
23. ↑ Simmons A, Aluvihare V, McMichael A. Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators. Immunity. 2001 Jun;14(6):763-77. PMID:11420046
24. ↑ Wolf D, Witte V, Laffert B, Blume K, Stromer E, Trapp S, d'Aloja P, Schurmann A, Baur AS. HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals. Nat Med. 2001 Nov;7(11):1217-24. PMID:11689886 doi:10.1038/nm1101-1217
25. ↑ Briggs SD, Sharkey M, Stevenson M, Smithgall TE. SH3-mediated Hck tyrosine kinase activation and fibroblast transformation by the Nef protein of HIV-1. J Biol Chem. 1997 Jul 18;272(29):17899-902. PMID:9218412
26. ↑ Xu XN, Laffert B, Screaton GR, Kraft M, Wolf D, Kolanus W, Mongkolsapay J, McMichael AJ, Baur AS. Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain. J Exp Med. 1999 May 3;189(9):1489-96. PMID:10224289
27. ↑ Kim YH, Chang SH, Kwon JH, Rhee SS. HIV-1 Nef plays an essential role in two independent processes in CD4 down-regulation: dissociation of the CD4-p56(lck) complex and targeting of CD4 to lysosomes. Virology. 1999 Apr 25;257(1):208-19. PMID:10208934 doi:S0042-6822(99)99642-3
28. ↑ Arora VK, Molina RP, Foster JL, Blakemore JL, Chernoff J, Fredericksen BL, Garcia JV. Lentivirus Nef specifically activates Pak2. J Virol. 2000 Dec;74(23):11081-7. PMID:11070003
29. ↑ Simmons A, Aluvihare V, McMichael A. Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators. Immunity. 2001 Jun;14(6):763-77. PMID:11420046
30. ↑ Wolf D, Witte V, Laffert B, Blume K, Stromer E, Trapp S, d'Aloja P, Schurmann A, Baur AS. HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals. Nat Med. 2001 Nov;7(11):1217-24. PMID:11689886 doi:10.1038/nm1101-1217
31. ↑ Alvarado JJ, Tarafdar S, Yeh JI, Smithgall TE. Interaction with the SH3-SH2 region of the Src-family kinase Hck structures the HIV-1 Nef dimer for kinase activation and effector recruitment. J Biol Chem. 2014 Aug 13. pii: jbc.M114.600031. PMID:25122770 doi:http://dx.doi.org/10.1074/jbc.M114.600031