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| ==Gasdermin D pore== | | ==Pore-forming protein== |
| <StructureSection load='6vfe' size='340' side='right'caption='[[6vfe]], [[Resolution|resolution]] 3.90Å' scene=''> | | <StructureSection load='6vfe' size='340' side='right'caption='[[6vfe]], [[Resolution|resolution]] 3.90Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[6vfe]] is a 33 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6VFE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VFE FirstGlance]. <br> | | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6VFE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VFE FirstGlance]. <br> |
| </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GSDMD, DFNA5L, GSDMDC1, FKSG10 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.9Å</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=6vfe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vfe OCA], [https://pdbe.org/6vfe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vfe RCSB], [https://www.ebi.ac.uk/pdbsum/6vfe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vfe ProSAT]</span></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=6vfe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vfe OCA], [https://pdbe.org/6vfe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vfe RCSB], [https://www.ebi.ac.uk/pdbsum/6vfe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vfe ProSAT]</span></td></tr> |
| </table> | | </table> |
| == Function ==
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| [[https://www.uniprot.org/uniprot/GSDMD_HUMAN GSDMD_HUMAN]] Gasdermin-D, N-terminal: Promotes pyroptosis in response to microbial infection and danger signals. Produced by the cleavage of gasdermin-D by inflammatory caspases CASP1 or CASP4 in response to canonical, as well as non-canonical (such as cytosolic LPS) inflammasome activators (PubMed:26375003, PubMed:26375259, PubMed:27418190). After cleavage, moves to the plasma membrane where it strongly binds to inner leaflet lipids, including monophosphorylated phosphatidylinositols, such as phosphatidylinositol 4-phosphate, bisphosphorylated phosphatidylinositols, such as phosphatidylinositol (4,5)-bisphosphate, as well as phosphatidylinositol (3,4,5)-bisphosphate, and more weakly to phosphatidic acid and phosphatidylserine (PubMed:27281216). Homooligomerizes within the membrane and forms pores of 10 - 15 nanometers (nm) of inner diameter, possibly allowing the release of mature IL1B and triggering pyroptosis (PubMed:27418190, PubMed:27281216). Exhibits bactericidal activity. Gasdermin-D, N-terminal released from pyroptotic cells into the extracellular milieu rapidly binds to and kills both Gram-negative and Gram-positive bacteria, without harming neighboring mammalian cells, as it does not disrupt the plasma membrane from the outside due to lipid-binding specificity (PubMed:27281216). Under cell culture conditions, also active against intracellular bacteria, such as Listeria monocytogenes (By similarity). Strongly binds to bacterial and mitochondrial lipids, including cardiolipin. Does not bind to unphosphorylated phosphatidylinositol, phosphatidylethanolamine nor phosphatidylcholine (PubMed:27281216).[UniProtKB:Q9D8T2]<ref>PMID:26375003</ref> <ref>PMID:26375259</ref> <ref>PMID:27281216</ref> <ref>PMID:27418190</ref>
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| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| As organelles of the innate immune system, inflammasomes activate caspase-1 and other inflammatory caspases that cleave gasdermin D (GSDMD). Caspase-1 also cleaves inactive precursors of the interleukin (IL)-1 family to generate mature cytokines such as IL-1beta and IL-18. Cleaved GSDMD forms transmembrane pores to enable the release of IL-1 and to drive cell lysis through pyroptosis(1-9). Here we report cryo-electron microscopy structures of the pore and the prepore of GSDMD. These structures reveal the different conformations of the two states, as well as extensive membrane-binding elements including a hydrophobic anchor and three positively charged patches. The GSDMD pore conduit is predominantly negatively charged. By contrast, IL-1 precursors have an acidic domain that is proteolytically removed by caspase-1(10). When permeabilized by GSDMD pores, unlysed liposomes release positively charged and neutral cargoes faster than negatively charged cargoes of similar sizes, and the pores favour the passage of IL-1beta and IL-18 over that of their precursors. Consistent with these findings, living-but not pyroptotic-macrophages preferentially release mature IL-1beta upon perforation by GSDMD. Mutation of the acidic residues of GSDMD compromises this preference, hindering intracellular retention of the precursor and secretion of the mature cytokine. The GSDMD pore therefore mediates IL-1 release by electrostatic filtering, which suggests the importance of charge in addition to size in the transport of cargoes across this large channel.
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| Gasdermin D pore structure reveals preferential release of mature interleukin-1.,Xia S, Zhang Z, Magupalli VG, Pablo JL, Dong Y, Vora SM, Wang L, Fu TM, Jacobson MP, Greka A, Lieberman J, Ruan J, Wu H Nature. 2021 Apr 21. pii: 10.1038/s41586-021-03478-3. doi:, 10.1038/s41586-021-03478-3. PMID:33883744<ref>PMID:33883744</ref>
| | ==See Also== |
| | | *[[Gasdermin 3D structures|Gasdermin 3D structures]] |
| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| <div class="pdbe-citations 6vfe" style="background-color:#fffaf0;"></div>
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| == References == | |
| <references/>
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| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Human]]
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| [[Category: Large Structures]] | | [[Category: Large Structures]] |
| [[Category: Ruan, J]] | | [[Category: Ruan J]] |
| [[Category: Wu, H]] | | [[Category: Wu H]] |
| [[Category: Xia, S]] | | [[Category: Xia S]] |
| [[Category: Lipid binding protein]]
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| [[Category: Pore-forming protein]]
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