| Structural highlights
Function
NEF_HV1BR 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] [7] [8] [9] [10] [11] 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).[12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] 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).[23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] 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).[34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] Extracellular Nef protein targets CD4(+) T-lymphocytes for apoptosis by interacting with CXCR4 surface receptors (By similarity).[45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
BACKGROUND: Human immunodeficiency virus (HIV) Nef protein accelerates virulent progression of acquired immunodeficiency syndrome (AIDS) by its interaction with specific cellular proteins involved in signal transduction and host cell activation. Nef has been shown to bind specifically to a subset of the Src family of kinases. The structures of free Nef and Nef bound to Src homology region 3 (SH3) domain are important for the elucidation of how the affinity and specificity for the Src kinase family SH3 domains are achieved, and also for the development of potential drugs and vaccines against AIDS. RESULTS: We have determined the crystal structures of the conserved core of HIV-1 Nef protein alone and in complex with the wild-type SH3 domain of the p59fyn protein tyrosine kinase (Fyn), at 3.0 A resolution. Comparison of the bound and unbound Nef structures revealed that a proline-rich motif (Pro-x-x-Pro), which is implicated in SH3 binding, is partially disordered in the absence of the binding partner; this motif only fully adopts a left-handed polyproline type II helix conformation upon complex formation with the Fyn SH3 domain. In addition, the structures show how an arginine residue (Arg77) of Nef interacts with Asp 100 of the so-called RT loop within the Fyn SH3 domain, and triggers a hydrogen-bond rearrangement which allows the loop to adapt to complement the Nef surface. The Arg96 residue of the Fyn SH3 domain is specifically accommodated in the same hydrophobic pocket of Nef as the isoleucine residue of a previously described Fyn SH3 (Arg96-->lle) mutant that binds to Nef with higher affinity than the wild type. CONCLUSIONS: The three-dimensional structures support evidence that the Nef-Fyn complex forms in vivo and may have a crucial role in the T cell perturbating action of Nef by altering T cell receptor signaling. The structures of bound and unbound Nef reveal that the multivalency of SH3 binding may be achieved by a ligand induced flexibility in the RT loop. The structures suggest possible targets for the design of inhibitors which specifically block Nef-SH3 interactions.
The crystal structure of HIV-1 Nef protein bound to the Fyn kinase SH3 domain suggests a role for this complex in altered T cell receptor signaling.,Arold S, Franken P, Strub MP, Hoh F, Benichou S, Benarous R, Dumas C Structure. 1997 Oct 15;5(10):1361-72. PMID:9351809[56]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Chowers MY, Spina CA, Kwoh TJ, Fitch NJ, Richman DD, Guatelli JC. Optimal infectivity in vitro of human immunodeficiency virus type 1 requires an intact nef gene. J Virol. 1994 May;68(5):2906-14. PMID:8151761
- ↑ Aiken C, Konner J, Landau NR, Lenburg ME, Trono D. Nef induces CD4 endocytosis: requirement for a critical dileucine motif in the membrane-proximal CD4 cytoplasmic domain. Cell. 1994 Mar 11;76(5):853-64. PMID:8124721
- ↑ Akari H, Arold S, Fukumori T, Okazaki T, Strebel K, Adachi A. Nef-induced major histocompatibility complex class I down-regulation is functionally dissociated from its virion incorporation, enhancement of viral infectivity, and CD4 down-regulation. J Virol. 2000 Mar;74(6):2907-12. PMID:10684310
- ↑ 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
- ↑ Swigut T, Shohdy N, Skowronski J. Mechanism for down-regulation of CD28 by Nef. EMBO J. 2001 Apr 2;20(7):1593-604. PMID:11285224 doi:http://dx.doi.org/10.1093/emboj/20.7.1593
- ↑ Geleziunas R, Xu W, Takeda K, Ichijo H, Greene WC. HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell. Nature. 2001 Apr 12;410(6830):834-8. PMID:11298454 doi:http://dx.doi.org/10.1038/35071111
- ↑ Greenway AL, McPhee DA, Allen K, Johnstone R, Holloway G, Mills J, Azad A, Sankovich S, Lambert P. Human immunodeficiency virus type 1 Nef binds to tumor suppressor p53 and protects cells against p53-mediated apoptosis. J Virol. 2002 Mar;76(6):2692-702. PMID:11861836
- ↑ Larsen JE, Massol RH, Nieland TJ, Kirchhausen T. HIV Nef-mediated major histocompatibility complex class I down-modulation is independent of Arf6 activity. Mol Biol Cell. 2004 Jan;15(1):323-31. Epub 2003 Nov 14. PMID:14617802 doi:http://dx.doi.org/10.1091/mbc.E03-08-0578
- ↑ Michel N, Allespach I, Venzke S, Fackler OT, Keppler OT. The Nef protein of human immunodeficiency virus establishes superinfection immunity by a dual strategy to downregulate cell-surface CCR5 and CD4. Curr Biol. 2005 Apr 26;15(8):714-23. PMID:15854903 doi:http://dx.doi.org/10.1016/j.cub.2005.02.058
- ↑ Venzke S, Michel N, Allespach I, Fackler OT, Keppler OT. Expression of Nef downregulates CXCR4, the major coreceptor of human immunodeficiency virus, from the surfaces of target cells and thereby enhances resistance to superinfection. J Virol. 2006 Nov;80(22):11141-52. Epub 2006 Aug 23. PMID:16928758 doi:http://dx.doi.org/10.1128/JVI.01556-06
- ↑ Hung CH, Thomas L, Ruby CE, Atkins KM, Morris NP, Knight ZA, Scholz I, Barklis E, Weinberg AD, Shokat KM, Thomas G. HIV-1 Nef assembles a Src family kinase-ZAP-70/Syk-PI3K cascade to downregulate cell-surface MHC-I. Cell Host Microbe. 2007 Apr 19;1(2):121-33. PMID:18005690 doi:http://dx.doi.org/10.1016/j.chom.2007.03.004
- ↑ Chowers MY, Spina CA, Kwoh TJ, Fitch NJ, Richman DD, Guatelli JC. Optimal infectivity in vitro of human immunodeficiency virus type 1 requires an intact nef gene. J Virol. 1994 May;68(5):2906-14. PMID:8151761
- ↑ Aiken C, Konner J, Landau NR, Lenburg ME, Trono D. Nef induces CD4 endocytosis: requirement for a critical dileucine motif in the membrane-proximal CD4 cytoplasmic domain. Cell. 1994 Mar 11;76(5):853-64. PMID:8124721
- ↑ Akari H, Arold S, Fukumori T, Okazaki T, Strebel K, Adachi A. Nef-induced major histocompatibility complex class I down-regulation is functionally dissociated from its virion incorporation, enhancement of viral infectivity, and CD4 down-regulation. J Virol. 2000 Mar;74(6):2907-12. PMID:10684310
- ↑ 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
- ↑ Swigut T, Shohdy N, Skowronski J. Mechanism for down-regulation of CD28 by Nef. EMBO J. 2001 Apr 2;20(7):1593-604. PMID:11285224 doi:http://dx.doi.org/10.1093/emboj/20.7.1593
- ↑ Geleziunas R, Xu W, Takeda K, Ichijo H, Greene WC. HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell. Nature. 2001 Apr 12;410(6830):834-8. PMID:11298454 doi:http://dx.doi.org/10.1038/35071111
- ↑ Greenway AL, McPhee DA, Allen K, Johnstone R, Holloway G, Mills J, Azad A, Sankovich S, Lambert P. Human immunodeficiency virus type 1 Nef binds to tumor suppressor p53 and protects cells against p53-mediated apoptosis. J Virol. 2002 Mar;76(6):2692-702. PMID:11861836
- ↑ Larsen JE, Massol RH, Nieland TJ, Kirchhausen T. HIV Nef-mediated major histocompatibility complex class I down-modulation is independent of Arf6 activity. Mol Biol Cell. 2004 Jan;15(1):323-31. Epub 2003 Nov 14. PMID:14617802 doi:http://dx.doi.org/10.1091/mbc.E03-08-0578
- ↑ Michel N, Allespach I, Venzke S, Fackler OT, Keppler OT. The Nef protein of human immunodeficiency virus establishes superinfection immunity by a dual strategy to downregulate cell-surface CCR5 and CD4. Curr Biol. 2005 Apr 26;15(8):714-23. PMID:15854903 doi:http://dx.doi.org/10.1016/j.cub.2005.02.058
- ↑ Venzke S, Michel N, Allespach I, Fackler OT, Keppler OT. Expression of Nef downregulates CXCR4, the major coreceptor of human immunodeficiency virus, from the surfaces of target cells and thereby enhances resistance to superinfection. J Virol. 2006 Nov;80(22):11141-52. Epub 2006 Aug 23. PMID:16928758 doi:http://dx.doi.org/10.1128/JVI.01556-06
- ↑ Hung CH, Thomas L, Ruby CE, Atkins KM, Morris NP, Knight ZA, Scholz I, Barklis E, Weinberg AD, Shokat KM, Thomas G. HIV-1 Nef assembles a Src family kinase-ZAP-70/Syk-PI3K cascade to downregulate cell-surface MHC-I. Cell Host Microbe. 2007 Apr 19;1(2):121-33. PMID:18005690 doi:http://dx.doi.org/10.1016/j.chom.2007.03.004
- ↑ Chowers MY, Spina CA, Kwoh TJ, Fitch NJ, Richman DD, Guatelli JC. Optimal infectivity in vitro of human immunodeficiency virus type 1 requires an intact nef gene. J Virol. 1994 May;68(5):2906-14. PMID:8151761
- ↑ Aiken C, Konner J, Landau NR, Lenburg ME, Trono D. Nef induces CD4 endocytosis: requirement for a critical dileucine motif in the membrane-proximal CD4 cytoplasmic domain. Cell. 1994 Mar 11;76(5):853-64. PMID:8124721
- ↑ Akari H, Arold S, Fukumori T, Okazaki T, Strebel K, Adachi A. Nef-induced major histocompatibility complex class I down-regulation is functionally dissociated from its virion incorporation, enhancement of viral infectivity, and CD4 down-regulation. J Virol. 2000 Mar;74(6):2907-12. PMID:10684310
- ↑ 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
- ↑ Swigut T, Shohdy N, Skowronski J. Mechanism for down-regulation of CD28 by Nef. EMBO J. 2001 Apr 2;20(7):1593-604. PMID:11285224 doi:http://dx.doi.org/10.1093/emboj/20.7.1593
- ↑ Geleziunas R, Xu W, Takeda K, Ichijo H, Greene WC. HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell. Nature. 2001 Apr 12;410(6830):834-8. PMID:11298454 doi:http://dx.doi.org/10.1038/35071111
- ↑ Greenway AL, McPhee DA, Allen K, Johnstone R, Holloway G, Mills J, Azad A, Sankovich S, Lambert P. Human immunodeficiency virus type 1 Nef binds to tumor suppressor p53 and protects cells against p53-mediated apoptosis. J Virol. 2002 Mar;76(6):2692-702. PMID:11861836
- ↑ Larsen JE, Massol RH, Nieland TJ, Kirchhausen T. HIV Nef-mediated major histocompatibility complex class I down-modulation is independent of Arf6 activity. Mol Biol Cell. 2004 Jan;15(1):323-31. Epub 2003 Nov 14. PMID:14617802 doi:http://dx.doi.org/10.1091/mbc.E03-08-0578
- ↑ Michel N, Allespach I, Venzke S, Fackler OT, Keppler OT. The Nef protein of human immunodeficiency virus establishes superinfection immunity by a dual strategy to downregulate cell-surface CCR5 and CD4. Curr Biol. 2005 Apr 26;15(8):714-23. PMID:15854903 doi:http://dx.doi.org/10.1016/j.cub.2005.02.058
- ↑ Venzke S, Michel N, Allespach I, Fackler OT, Keppler OT. Expression of Nef downregulates CXCR4, the major coreceptor of human immunodeficiency virus, from the surfaces of target cells and thereby enhances resistance to superinfection. J Virol. 2006 Nov;80(22):11141-52. Epub 2006 Aug 23. PMID:16928758 doi:http://dx.doi.org/10.1128/JVI.01556-06
- ↑ Hung CH, Thomas L, Ruby CE, Atkins KM, Morris NP, Knight ZA, Scholz I, Barklis E, Weinberg AD, Shokat KM, Thomas G. HIV-1 Nef assembles a Src family kinase-ZAP-70/Syk-PI3K cascade to downregulate cell-surface MHC-I. Cell Host Microbe. 2007 Apr 19;1(2):121-33. PMID:18005690 doi:http://dx.doi.org/10.1016/j.chom.2007.03.004
- ↑ Chowers MY, Spina CA, Kwoh TJ, Fitch NJ, Richman DD, Guatelli JC. Optimal infectivity in vitro of human immunodeficiency virus type 1 requires an intact nef gene. J Virol. 1994 May;68(5):2906-14. PMID:8151761
- ↑ Aiken C, Konner J, Landau NR, Lenburg ME, Trono D. Nef induces CD4 endocytosis: requirement for a critical dileucine motif in the membrane-proximal CD4 cytoplasmic domain. Cell. 1994 Mar 11;76(5):853-64. PMID:8124721
- ↑ Akari H, Arold S, Fukumori T, Okazaki T, Strebel K, Adachi A. Nef-induced major histocompatibility complex class I down-regulation is functionally dissociated from its virion incorporation, enhancement of viral infectivity, and CD4 down-regulation. J Virol. 2000 Mar;74(6):2907-12. PMID:10684310
- ↑ 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
- ↑ Swigut T, Shohdy N, Skowronski J. Mechanism for down-regulation of CD28 by Nef. EMBO J. 2001 Apr 2;20(7):1593-604. PMID:11285224 doi:http://dx.doi.org/10.1093/emboj/20.7.1593
- ↑ Geleziunas R, Xu W, Takeda K, Ichijo H, Greene WC. HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell. Nature. 2001 Apr 12;410(6830):834-8. PMID:11298454 doi:http://dx.doi.org/10.1038/35071111
- ↑ Greenway AL, McPhee DA, Allen K, Johnstone R, Holloway G, Mills J, Azad A, Sankovich S, Lambert P. Human immunodeficiency virus type 1 Nef binds to tumor suppressor p53 and protects cells against p53-mediated apoptosis. J Virol. 2002 Mar;76(6):2692-702. PMID:11861836
- ↑ Larsen JE, Massol RH, Nieland TJ, Kirchhausen T. HIV Nef-mediated major histocompatibility complex class I down-modulation is independent of Arf6 activity. Mol Biol Cell. 2004 Jan;15(1):323-31. Epub 2003 Nov 14. PMID:14617802 doi:http://dx.doi.org/10.1091/mbc.E03-08-0578
- ↑ Michel N, Allespach I, Venzke S, Fackler OT, Keppler OT. The Nef protein of human immunodeficiency virus establishes superinfection immunity by a dual strategy to downregulate cell-surface CCR5 and CD4. Curr Biol. 2005 Apr 26;15(8):714-23. PMID:15854903 doi:http://dx.doi.org/10.1016/j.cub.2005.02.058
- ↑ Venzke S, Michel N, Allespach I, Fackler OT, Keppler OT. Expression of Nef downregulates CXCR4, the major coreceptor of human immunodeficiency virus, from the surfaces of target cells and thereby enhances resistance to superinfection. J Virol. 2006 Nov;80(22):11141-52. Epub 2006 Aug 23. PMID:16928758 doi:http://dx.doi.org/10.1128/JVI.01556-06
- ↑ Hung CH, Thomas L, Ruby CE, Atkins KM, Morris NP, Knight ZA, Scholz I, Barklis E, Weinberg AD, Shokat KM, Thomas G. HIV-1 Nef assembles a Src family kinase-ZAP-70/Syk-PI3K cascade to downregulate cell-surface MHC-I. Cell Host Microbe. 2007 Apr 19;1(2):121-33. PMID:18005690 doi:http://dx.doi.org/10.1016/j.chom.2007.03.004
- ↑ Chowers MY, Spina CA, Kwoh TJ, Fitch NJ, Richman DD, Guatelli JC. Optimal infectivity in vitro of human immunodeficiency virus type 1 requires an intact nef gene. J Virol. 1994 May;68(5):2906-14. PMID:8151761
- ↑ Aiken C, Konner J, Landau NR, Lenburg ME, Trono D. Nef induces CD4 endocytosis: requirement for a critical dileucine motif in the membrane-proximal CD4 cytoplasmic domain. Cell. 1994 Mar 11;76(5):853-64. PMID:8124721
- ↑ Akari H, Arold S, Fukumori T, Okazaki T, Strebel K, Adachi A. Nef-induced major histocompatibility complex class I down-regulation is functionally dissociated from its virion incorporation, enhancement of viral infectivity, and CD4 down-regulation. J Virol. 2000 Mar;74(6):2907-12. PMID:10684310
- ↑ 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
- ↑ Swigut T, Shohdy N, Skowronski J. Mechanism for down-regulation of CD28 by Nef. EMBO J. 2001 Apr 2;20(7):1593-604. PMID:11285224 doi:http://dx.doi.org/10.1093/emboj/20.7.1593
- ↑ Geleziunas R, Xu W, Takeda K, Ichijo H, Greene WC. HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell. Nature. 2001 Apr 12;410(6830):834-8. PMID:11298454 doi:http://dx.doi.org/10.1038/35071111
- ↑ Greenway AL, McPhee DA, Allen K, Johnstone R, Holloway G, Mills J, Azad A, Sankovich S, Lambert P. Human immunodeficiency virus type 1 Nef binds to tumor suppressor p53 and protects cells against p53-mediated apoptosis. J Virol. 2002 Mar;76(6):2692-702. PMID:11861836
- ↑ Larsen JE, Massol RH, Nieland TJ, Kirchhausen T. HIV Nef-mediated major histocompatibility complex class I down-modulation is independent of Arf6 activity. Mol Biol Cell. 2004 Jan;15(1):323-31. Epub 2003 Nov 14. PMID:14617802 doi:http://dx.doi.org/10.1091/mbc.E03-08-0578
- ↑ Michel N, Allespach I, Venzke S, Fackler OT, Keppler OT. The Nef protein of human immunodeficiency virus establishes superinfection immunity by a dual strategy to downregulate cell-surface CCR5 and CD4. Curr Biol. 2005 Apr 26;15(8):714-23. PMID:15854903 doi:http://dx.doi.org/10.1016/j.cub.2005.02.058
- ↑ Venzke S, Michel N, Allespach I, Fackler OT, Keppler OT. Expression of Nef downregulates CXCR4, the major coreceptor of human immunodeficiency virus, from the surfaces of target cells and thereby enhances resistance to superinfection. J Virol. 2006 Nov;80(22):11141-52. Epub 2006 Aug 23. PMID:16928758 doi:http://dx.doi.org/10.1128/JVI.01556-06
- ↑ Hung CH, Thomas L, Ruby CE, Atkins KM, Morris NP, Knight ZA, Scholz I, Barklis E, Weinberg AD, Shokat KM, Thomas G. HIV-1 Nef assembles a Src family kinase-ZAP-70/Syk-PI3K cascade to downregulate cell-surface MHC-I. Cell Host Microbe. 2007 Apr 19;1(2):121-33. PMID:18005690 doi:http://dx.doi.org/10.1016/j.chom.2007.03.004
- ↑ Arold S, Franken P, Strub MP, Hoh F, Benichou S, Benarous R, Dumas C. The crystal structure of HIV-1 Nef protein bound to the Fyn kinase SH3 domain suggests a role for this complex in altered T cell receptor signaling. Structure. 1997 Oct 15;5(10):1361-72. PMID:9351809
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