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| | ==Crystal structure of SIVmac239 Nef bound to an engineered Hck SH3 domain== | | ==Crystal structure of SIVmac239 Nef bound to an engineered Hck SH3 domain== |
| - | <StructureSection load='5nuh' size='340' side='right' caption='[[5nuh]], [[Resolution|resolution]] 2.78Å' scene=''> | + | <StructureSection load='5nuh' size='340' side='right'caption='[[5nuh]], [[Resolution|resolution]] 2.78Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5nuh]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NUH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NUH FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5nuh]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Simian_immunodeficiency_virus Simian immunodeficiency virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NUH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5NUH FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=GLX:GLU/GLN+AMBIGUOUS'>GLX</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.78Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5nui|5nui]]</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5nuh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nuh OCA], [https://pdbe.org/5nuh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5nuh RCSB], [https://www.ebi.ac.uk/pdbsum/5nuh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5nuh ProSAT]</span></td></tr> |
| - | <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=5nuh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nuh OCA], [http://pdbe.org/5nuh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nuh RCSB], [http://www.ebi.ac.uk/pdbsum/5nuh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nuh ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| - | == Disease == | |
| - | [[http://www.uniprot.org/uniprot/HCK_HUMAN HCK_HUMAN]] Note=Aberrant activation of HCK by HIV-1 protein Nef enhances HIV-1 replication and contributes to HIV-1 pathogenicity.<ref>PMID:19114024</ref> <ref>PMID:20452982</ref> Note=Aberrant activation of HCK, e.g. by the BCR-ABL fusion protein, promotes cancer cell proliferation.<ref>PMID:19114024</ref> <ref>PMID:20452982</ref> | |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/HCK_HUMAN HCK_HUMAN]] Non-receptor tyrosine-protein kinase found in hematopoietic cells that transmits signals from cell surface receptors and plays an important role in the regulation of innate immune responses, including neutrophil, monocyte, macrophage and mast cell functions, phagocytosis, cell survival and proliferation, cell adhesion and migration. Acts downstream of receptors that bind the Fc region of immunoglobulins, such as FCGR1A and FCGR2A, but also CSF3R, PLAUR, the receptors for IFNG, IL2, IL6 and IL8, and integrins, such as ITGB1 and ITGB2. During the phagocytic process, mediates mobilization of secretory lysosomes, degranulation, and activation of NADPH oxidase to bring about the respiratory burst. Plays a role in the release of inflammatory molecules. Promotes reorganization of the actin cytoskeleton and actin polymerization, formation of podosomes and cell protrusions. Inhibits TP73-mediated transcription activation and TP73-mediated apoptosis. Phosphorylates CBL in response to activation of immunoglobulin gamma Fc region receptors. Phosphorylates ADAM15, BCR, ELMO1, FCGR2A, GAB1, GAB2, RAPGEF1, STAT5B, TP73, VAV1 and WAS.<ref>PMID:8132624</ref> <ref>PMID:7535819</ref> <ref>PMID:9406996</ref> <ref>PMID:9407116</ref> <ref>PMID:10092522</ref> <ref>PMID:10779760</ref> <ref>PMID:10973280</ref> <ref>PMID:12411494</ref> <ref>PMID:11741929</ref> <ref>PMID:11904303</ref> <ref>PMID:11896602</ref> <ref>PMID:15010462</ref> <ref>PMID:15952790</ref> <ref>PMID:15998323</ref> <ref>PMID:17535448</ref> <ref>PMID:17310994</ref> <ref>PMID:19114024</ref> <ref>PMID:19903482</ref> <ref>PMID:20452982</ref> | + | [https://www.uniprot.org/uniprot/Q5QGG3_SIV Q5QGG3_SIV] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5nuh" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5nuh" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Protein Nef 3D structures|Protein Nef 3D structures]] |
| | + | *[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Anand, K]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Geyer, M]] | + | [[Category: Large Structures]] |
| - | [[Category: Horenkamp, F A]] | + | [[Category: Simian immunodeficiency virus]] |
| - | [[Category: Nef]] | + | [[Category: Anand K]] |
| - | [[Category: Sh3]] | + | [[Category: Geyer M]] |
| - | [[Category: Siv]] | + | [[Category: Horenkamp FA]] |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Virus]]
| + | |
| Structural highlights
Function
Q5QGG3_SIV
Publication Abstract from PubMed
Lentiviral Nefs recruit assembly polypeptide complexes and target sorting motifs in cellular receptors to induce their internalization. While Nef-mediated CD4 downmodulation is conserved, the ability to internalize CD3 was lost in HIV-1 and its precursors. Although both functions play key roles in lentiviral replication and pathogenicity, the underlying structural requirements are poorly defined. Here, we determine the structure of SIVmac239 Nef bound to the ExxxLM motif of another Nef molecule at 2.5 A resolution. This provides a basis for a structural model, where a hydrophobic crevice in simian immunodeficiency virus (SIV) Nef targets a dileucine motif in CD4 and a tyrosine-based motif in CD3. Introducing key residues into this crevice of HIV-1 Nef enables CD3 binding but an additional N-terminal tyrosine motif is required for internalization. Our resolution of the CD4/Nef/AP2 complex and generation of HIV-1 Nefs capable of CD3 downregulation provide insights into sorting motif interactions and target discrimination of Nef.HIV and simian immunodeficiency virus (SIV) Nef proteins both stimulate the clathrin-mediated endocytosis of CD4 but differ in downmodulation of the immune receptor CD3. Here, the authors present the structure of SIV Nef bound to the ExxxLM motif of another Nef molecule, which allows them to propose a model how Nef recognizes these motifs in CD3 and CD4.
Endocytic sorting motif interactions involved in Nef-mediated downmodulation of CD4 and CD3.,Manrique S, Sauter D, Horenkamp FA, Lulf S, Yu H, Hotter D, Anand K, Kirchhoff F, Geyer M Nat Commun. 2017 Sep 5;8(1):442. doi: 10.1038/s41467-017-00481-z. PMID:28874665[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Manrique S, Sauter D, Horenkamp FA, Lulf S, Yu H, Hotter D, Anand K, Kirchhoff F, Geyer M. Endocytic sorting motif interactions involved in Nef-mediated downmodulation of CD4 and CD3. Nat Commun. 2017 Sep 5;8(1):442. doi: 10.1038/s41467-017-00481-z. PMID:28874665 doi:http://dx.doi.org/10.1038/s41467-017-00481-z
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