4d8d

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==Crystal structure of HIV-1 NEF Fyn-SH3 R96W variant==
==Crystal structure of HIV-1 NEF Fyn-SH3 R96W variant==
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<StructureSection load='4d8d' size='340' side='right' caption='[[4d8d]], [[Resolution|resolution]] 2.52&Aring;' scene=''>
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<StructureSection load='4d8d' size='340' side='right'caption='[[4d8d]], [[Resolution|resolution]] 2.52&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4d8d]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Hiv-1 Hiv-1] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4D8D OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4D8D FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4d8d]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Hiv-1 Hiv-1] and [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4D8D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4D8D 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=GOL:GLYCEROL'>GOL</scene></td></tr>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3h0f|3h0f]], [[3h0i|3h0i]], [[3h0h|3h0h]]</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3h0f|3h0f]], [[3h0i|3h0i]], [[3h0h|3h0h]]</div></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FYN, FYN TYROSINE KINASE ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), nef ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11686 HIV-1])</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FYN, FYN TYROSINE KINASE ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), nef ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11686 HIV-1])</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></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=4d8d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d8d OCA], [http://pdbe.org/4d8d PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4d8d RCSB], [http://www.ebi.ac.uk/pdbsum/4d8d PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4d8d ProSAT]</span></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=4d8d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d8d OCA], [https://pdbe.org/4d8d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4d8d RCSB], [https://www.ebi.ac.uk/pdbsum/4d8d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4d8d ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/FYN_HUMAN FYN_HUMAN]] Non-receptor tyrosine-protein kinase that plays a role in many biological processes including regulation of cell growth and survival, cell adhesion, integrin-mediated signaling, cytoskeletal remodeling, cell motility, immune response and axon guidance. Inactive FYN is phosphorylated on its C-terminal tail within the catalytic domain. Following activation by PKA, the protein subsequently associates with PTK2/FAK1, allowing PTK2/FAK1 phosphorylation, activation and targeting to focal adhesions. Involved in the regulation of cell adhesion and motility through phosphorylation of CTNNB1 (beta-catenin) and CTNND1 (delta-catenin). Regulates cytoskeletal remodeling by phosphorylating several proteins including the actin regulator WAS and the microtubule-associated proteins MAP2 and MAPT. Promotes cell survival by phosphorylating AGAP2/PIKE-A and preventing its apoptotic cleavage. Participates in signal transduction pathways that regulate the integrity of the glomerular slit diaphragm (an essential part of the glomerular filter of the kidney) by phosphorylating several slit diaphragm components including NPHS1, KIRREL and TRPC6. Plays a role in neural processes by phosphorylating DPYSL2, a multifunctional adapter protein within the central nervous system, ARHGAP32, a regulator for Rho family GTPases implicated in various neural functions, and SNCA, a small pre-synaptic protein. Participates in the downstream signaling pathways that lead to T-cell differentiation and proliferation following T-cell receptor (TCR) stimulation. Also participates in negative feedback regulation of TCR signaling through phosphorylation of PAG1, thereby promoting interaction between PAG1 and CSK and recruitment of CSK to lipid rafts. CSK maintains LCK and FYN in an inactive form. Promotes CD28-induced phosphorylation of VAV1.<ref>PMID:7822789</ref> <ref>PMID:7568038</ref> <ref>PMID:11005864</ref> <ref>PMID:11162638</ref> <ref>PMID:11536198</ref> <ref>PMID:12788081</ref> <ref>PMID:12640114</ref> <ref>PMID:14761972</ref> <ref>PMID:15557120</ref> <ref>PMID:14707117</ref> <ref>PMID:15536091</ref> <ref>PMID:16387660</ref> <ref>PMID:16841086</ref> <ref>PMID:17194753</ref> <ref>PMID:18056706</ref> <ref>PMID:18258597</ref> <ref>PMID:19179337</ref> <ref>PMID:19652227</ref> <ref>PMID:20100835</ref> [[http://www.uniprot.org/uniprot/NEF_HV1BR 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).<ref>PMID:8151761</ref> <ref>PMID:8124721</ref> <ref>PMID:10684310</ref> <ref>PMID:11070003</ref> <ref>PMID:11285224</ref> <ref>PMID:11298454</ref> <ref>PMID:11861836</ref> <ref>PMID:14617802</ref> <ref>PMID:15854903</ref> <ref>PMID:16928758</ref> <ref>PMID:18005690</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).<ref>PMID:8151761</ref> <ref>PMID:8124721</ref> <ref>PMID:10684310</ref> <ref>PMID:11070003</ref> <ref>PMID:11285224</ref> <ref>PMID:11298454</ref> <ref>PMID:11861836</ref> <ref>PMID:14617802</ref> <ref>PMID:15854903</ref> <ref>PMID:16928758</ref> <ref>PMID:18005690</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:8151761</ref> <ref>PMID:8124721</ref> <ref>PMID:10684310</ref> <ref>PMID:11070003</ref> <ref>PMID:11285224</ref> <ref>PMID:11298454</ref> <ref>PMID:11861836</ref> <ref>PMID:14617802</ref> <ref>PMID:15854903</ref> <ref>PMID:16928758</ref> <ref>PMID:18005690</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:8151761</ref> <ref>PMID:8124721</ref> <ref>PMID:10684310</ref> <ref>PMID:11070003</ref> <ref>PMID:11285224</ref> <ref>PMID:11298454</ref> <ref>PMID:11861836</ref> <ref>PMID:14617802</ref> <ref>PMID:15854903</ref> <ref>PMID:16928758</ref> <ref>PMID:18005690</ref> Extracellular Nef protein targets CD4(+) T-lymphocytes for apoptosis by interacting with CXCR4 surface receptors (By similarity).<ref>PMID:8151761</ref> <ref>PMID:8124721</ref> <ref>PMID:10684310</ref> <ref>PMID:11070003</ref> <ref>PMID:11285224</ref> <ref>PMID:11298454</ref> <ref>PMID:11861836</ref> <ref>PMID:14617802</ref> <ref>PMID:15854903</ref> <ref>PMID:16928758</ref> <ref>PMID:18005690</ref>
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[[https://www.uniprot.org/uniprot/FYN_HUMAN FYN_HUMAN]] Non-receptor tyrosine-protein kinase that plays a role in many biological processes including regulation of cell growth and survival, cell adhesion, integrin-mediated signaling, cytoskeletal remodeling, cell motility, immune response and axon guidance. Inactive FYN is phosphorylated on its C-terminal tail within the catalytic domain. Following activation by PKA, the protein subsequently associates with PTK2/FAK1, allowing PTK2/FAK1 phosphorylation, activation and targeting to focal adhesions. Involved in the regulation of cell adhesion and motility through phosphorylation of CTNNB1 (beta-catenin) and CTNND1 (delta-catenin). Regulates cytoskeletal remodeling by phosphorylating several proteins including the actin regulator WAS and the microtubule-associated proteins MAP2 and MAPT. Promotes cell survival by phosphorylating AGAP2/PIKE-A and preventing its apoptotic cleavage. Participates in signal transduction pathways that regulate the integrity of the glomerular slit diaphragm (an essential part of the glomerular filter of the kidney) by phosphorylating several slit diaphragm components including NPHS1, KIRREL and TRPC6. Plays a role in neural processes by phosphorylating DPYSL2, a multifunctional adapter protein within the central nervous system, ARHGAP32, a regulator for Rho family GTPases implicated in various neural functions, and SNCA, a small pre-synaptic protein. Participates in the downstream signaling pathways that lead to T-cell differentiation and proliferation following T-cell receptor (TCR) stimulation. Also participates in negative feedback regulation of TCR signaling through phosphorylation of PAG1, thereby promoting interaction between PAG1 and CSK and recruitment of CSK to lipid rafts. CSK maintains LCK and FYN in an inactive form. Promotes CD28-induced phosphorylation of VAV1.<ref>PMID:7822789</ref> <ref>PMID:7568038</ref> <ref>PMID:11005864</ref> <ref>PMID:11162638</ref> <ref>PMID:11536198</ref> <ref>PMID:12788081</ref> <ref>PMID:12640114</ref> <ref>PMID:14761972</ref> <ref>PMID:15557120</ref> <ref>PMID:14707117</ref> <ref>PMID:15536091</ref> <ref>PMID:16387660</ref> <ref>PMID:16841086</ref> <ref>PMID:17194753</ref> <ref>PMID:18056706</ref> <ref>PMID:18258597</ref> <ref>PMID:19179337</ref> <ref>PMID:19652227</ref> <ref>PMID:20100835</ref> [[https://www.uniprot.org/uniprot/NEF_HV1BR 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).<ref>PMID:8151761</ref> <ref>PMID:8124721</ref> <ref>PMID:10684310</ref> <ref>PMID:11070003</ref> <ref>PMID:11285224</ref> <ref>PMID:11298454</ref> <ref>PMID:11861836</ref> <ref>PMID:14617802</ref> <ref>PMID:15854903</ref> <ref>PMID:16928758</ref> <ref>PMID:18005690</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).<ref>PMID:8151761</ref> <ref>PMID:8124721</ref> <ref>PMID:10684310</ref> <ref>PMID:11070003</ref> <ref>PMID:11285224</ref> <ref>PMID:11298454</ref> <ref>PMID:11861836</ref> <ref>PMID:14617802</ref> <ref>PMID:15854903</ref> <ref>PMID:16928758</ref> <ref>PMID:18005690</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:8151761</ref> <ref>PMID:8124721</ref> <ref>PMID:10684310</ref> <ref>PMID:11070003</ref> <ref>PMID:11285224</ref> <ref>PMID:11298454</ref> <ref>PMID:11861836</ref> <ref>PMID:14617802</ref> <ref>PMID:15854903</ref> <ref>PMID:16928758</ref> <ref>PMID:18005690</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:8151761</ref> <ref>PMID:8124721</ref> <ref>PMID:10684310</ref> <ref>PMID:11070003</ref> <ref>PMID:11285224</ref> <ref>PMID:11298454</ref> <ref>PMID:11861836</ref> <ref>PMID:14617802</ref> <ref>PMID:15854903</ref> <ref>PMID:16928758</ref> <ref>PMID:18005690</ref> Extracellular Nef protein targets CD4(+) T-lymphocytes for apoptosis by interacting with CXCR4 surface receptors (By similarity).<ref>PMID:8151761</ref> <ref>PMID:8124721</ref> <ref>PMID:10684310</ref> <ref>PMID:11070003</ref> <ref>PMID:11285224</ref> <ref>PMID:11298454</ref> <ref>PMID:11861836</ref> <ref>PMID:14617802</ref> <ref>PMID:15854903</ref> <ref>PMID:16928758</ref> <ref>PMID:18005690</ref>
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<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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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--&gt;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.
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The Nef protein of human and simian immunodeficiency viruses boosts viral pathogenicity through its interactions with host cell proteins. By combining the polyvalency of its large unstructured regions with the binding selectivity and strength of its folded core domain, Nef can associate with many different host cell proteins, thereby disrupting their functions. For example, the combination of a linear proline-rich motif and hydrophobic core domain surface allows Nef to bind tightly and specifically to SH3 domains of Src family kinases. We investigated whether the interplay between Nef's flexible regions and its core domain could allosterically influence ligand selection. We found that the flexible regions can associate with the core domain in different ways, producing distinct conformational states that alter the way in which Nef selects for SH3 domains and exposes some of its binding motifs. The ensuing crosstalk between ligands might promote functionally coherent Nef-bound protein ensembles by synergizing certain subsets of ligands while excluding others. We also combined proteomic and bioinformatics analyses to identify human proteins that select SH3 domains in the same way as Nef. We found that only 3% of clones from a whole-human fetal library displayed Nef-like SH3 selectivity. However, in most cases, this selectivity appears to be achieved by a canonical linear interaction rather than by a Nef-like 'tertiary' interaction. Our analysis supports the contention that Nef's mode of hijacking SH3 domains is a virus-specific adaptation with no or very few cellular counterparts. Thus, the Nef tertiary binding surface is a promising virus-specific drug target.
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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<ref>PMID:9351809</ref>
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Synergy and allostery in ligand binding by HIV-1 Nef.,Aldehaiman A, Momin AA, Restouin A, Wang L, Shi X, Aljedani S, Opi S, Lugari A, Shahul Hameed UF, Ponchon L, Morelli X, Huang M, Dumas C, Collette Y, Arold ST Biochem J. 2021 Apr 30;478(8):1525-1545. doi: 10.1042/BCJ20201002. PMID:33787846<ref>PMID:33787846</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 4d8d" style="background-color:#fffaf0;"></div>
<div class="pdbe-citations 4d8d" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Protein Nef|Protein Nef]]
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*[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]]
== References ==
== References ==
<references/>
<references/>
Line 27: Line 31:
[[Category: Hiv-1]]
[[Category: Hiv-1]]
[[Category: Human]]
[[Category: Human]]
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[[Category: Large Structures]]
[[Category: Non-specific protein-tyrosine kinase]]
[[Category: Non-specific protein-tyrosine kinase]]
[[Category: Arold, S T]]
[[Category: Arold, S T]]

Revision as of 20:10, 20 October 2021

Crystal structure of HIV-1 NEF Fyn-SH3 R96W variant

PDB ID 4d8d

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