6b72

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==A novel HIV-1 Nef dimer interface induced by a single octyl-glucoside molecule==
==A novel HIV-1 Nef dimer interface induced by a single octyl-glucoside molecule==
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<StructureSection load='6b72' size='340' side='right' caption='[[6b72]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
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<StructureSection load='6b72' size='340' side='right'caption='[[6b72]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6b72]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6B72 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6B72 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6b72]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/HIV-1_M:B_ARV2/SF2 HIV-1 M:B_ARV2/SF2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6B72 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6B72 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.2&#8491;</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6b72 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b72 OCA], [http://pdbe.org/6b72 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6b72 RCSB], [http://www.ebi.ac.uk/pdbsum/6b72 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6b72 ProSAT]</span></td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6b72 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b72 OCA], [https://pdbe.org/6b72 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6b72 RCSB], [https://www.ebi.ac.uk/pdbsum/6b72 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6b72 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/NEF_HV1A2 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).<ref>PMID:9218412</ref> <ref>PMID:10224289</ref> <ref>PMID:10208934</ref> <ref>PMID:11070003</ref> <ref>PMID:11420046</ref> <ref>PMID:11689886</ref> 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).<ref>PMID:9218412</ref> <ref>PMID:10224289</ref> <ref>PMID:10208934</ref> <ref>PMID:11070003</ref> <ref>PMID:11420046</ref> <ref>PMID:11689886</ref> 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).<ref>PMID:9218412</ref> <ref>PMID:10224289</ref> <ref>PMID:10208934</ref> <ref>PMID:11070003</ref> <ref>PMID:11420046</ref> <ref>PMID:11689886</ref> 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).<ref>PMID:9218412</ref> <ref>PMID:10224289</ref> <ref>PMID:10208934</ref> <ref>PMID:11070003</ref> <ref>PMID:11420046</ref> <ref>PMID:11689886</ref> Extracellular Nef protein targets CD4(+) T-lymphocytes for apoptosis by interacting with CXCR4 surface receptors (By similarity).<ref>PMID:9218412</ref> <ref>PMID:10224289</ref> <ref>PMID:10208934</ref> <ref>PMID:11070003</ref> <ref>PMID:11420046</ref> <ref>PMID:11689886</ref>
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[https://www.uniprot.org/uniprot/NEF_HV1A2 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).<ref>PMID:9218412</ref> <ref>PMID:10224289</ref> <ref>PMID:10208934</ref> <ref>PMID:11070003</ref> <ref>PMID:11420046</ref> <ref>PMID:11689886</ref> 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).<ref>PMID:9218412</ref> <ref>PMID:10224289</ref> <ref>PMID:10208934</ref> <ref>PMID:11070003</ref> <ref>PMID:11420046</ref> <ref>PMID:11689886</ref> 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).<ref>PMID:9218412</ref> <ref>PMID:10224289</ref> <ref>PMID:10208934</ref> <ref>PMID:11070003</ref> <ref>PMID:11420046</ref> <ref>PMID:11689886</ref> 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).<ref>PMID:9218412</ref> <ref>PMID:10224289</ref> <ref>PMID:10208934</ref> <ref>PMID:11070003</ref> <ref>PMID:11420046</ref> <ref>PMID:11689886</ref> Extracellular Nef protein targets CD4(+) T-lymphocytes for apoptosis by interacting with CXCR4 surface receptors (By similarity).<ref>PMID:9218412</ref> <ref>PMID:10224289</ref> <ref>PMID:10208934</ref> <ref>PMID:11070003</ref> <ref>PMID:11420046</ref> <ref>PMID:11689886</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The HIV-1 Nef accessory protein is essential for viral pathogenicity and AIDS progression. Nef forms complexes with multiple host cell factors to facilitate viral replication and promote immune escape of HIV-infected cells. Previous X-ray crystal structures demonstrate that Nef forms homodimers, the orientation of which are influenced by host cell binding partners. In cell-based fluorescence complementation assays, Nef forms homodimers at the plasma membrane. However, recombinant Nef proteins often exist as monomers in solution, suggesting that membrane interaction may also trigger monomer to dimer transitions. In this study, we show that monomeric Nef core proteins can be induced to form dimers in the presence of low concentrations of the non-ionic surfactant, beta-octyl glucoside (betaOG). X-ray crystallography revealed that a single betaOG molecule is present in the Nef dimer, with the 8-carbon acyl chain of the ligand binding to a hydrophobic pocket formed by the dimer interface. This Nef-betaOG dimer interface involves helix alphaB, as observed in previous dimer structures, as well as a helix formed by N-terminal residues 54-66. Nef dimer formation is stabilized in solution by the addition of betaOG, providing biochemical validation for the crystal structure. These observations together suggest that the interaction with host cell lipid mediators or other hydrophobic ligands may play a role in Nef dimerization, which has been previously linked to multiple Nef functions including host cell protein kinase activation, CD4 downregulation, and enhancement of HIV-1 replication.
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A single beta-octyl glucoside molecule induces HIV-1 Nef dimer formation in the absence of partner protein binding.,Wu M, Alvarado JJ, Augelli-Szafran CE, Ptak RG, Smithgall TE PLoS One. 2018 Feb 7;13(2):e0192512. doi: 10.1371/journal.pone.0192512., eCollection 2018. PMID:29415006<ref>PMID:29415006</ref>
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==See Also==
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*[[Protein Nef 3D structures|Protein Nef 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 6b72" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Augelli-Szafran, C E]]
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[[Category: HIV-1 M:B_ARV2/SF2]]
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[[Category: Ptak, R G]]
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[[Category: Large Structures]]
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[[Category: Smithgall, T E]]
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[[Category: Augelli-Szafran CE]]
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[[Category: Wu, M]]
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[[Category: Ptak RG]]
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[[Category: Dimer]]
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[[Category: Smithgall TE]]
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[[Category: Hiv-1 nef]]
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[[Category: Wu M]]
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[[Category: Viral protein]]
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Current revision

A novel HIV-1 Nef dimer interface induced by a single octyl-glucoside molecule

PDB ID 6b72

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