View source for 8gtn


==Cryo-EM structure of the gasdermin B pore==
<StructureSection load='8gtn' size='340' side='right'caption='[[8gtn]], [[Resolution|resolution]] 3.17&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8gtn]] is a 27 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8GTN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8GTN FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.17&#8491;</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=8gtn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8gtn OCA], [https://pdbe.org/8gtn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8gtn RCSB], [https://www.ebi.ac.uk/pdbsum/8gtn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8gtn ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/GSDMB_HUMAN GSDMB_HUMAN] Precursor of a pore-forming protein that acts as a downstream mediator of granzyme-mediated cell death (PubMed:32299851). This form constitutes the precursor of the pore-forming protein: upon cleavage, the released N-terminal moiety (Gasdermin-B, N-terminal) binds to membranes and forms pores, triggering pyroptosis (PubMed:32299851). Also acts as a regulator of epithelial cell repair independently of programmed cell death: translocates to the plasma membrane and promotes epithelial maintenance and repair by regulating PTK2/FAK-mediated phosphorylation of PDGFA (PubMed:35021065).<ref>PMID:32299851</ref> <ref>PMID:35021065</ref>   Pore-forming protein produced by cleavage by granzyme A (GZMA), which causes membrane permeabilization and pyroptosis in target cells of cytotoxic T and natural killer (NK) cells (PubMed:27281216, PubMed:32299851). Key downstream mediator of granzyme-mediated cell death: (1) granzyme A (GZMA), delivered to target cells from cytotoxic T- and NK-cells, (2) specifically cleaves Gasdermin-B to generate this form (PubMed:32299851). After cleavage, moves to the plasma membrane, homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, triggering pyroptosis (PubMed:32299851, PubMed:36599845, PubMed:36991122, PubMed:36991125). The different isoforms recognize and bind different phospholipids on membranes, promoting cell death of different target cells (PubMed:34022140, PubMed:36157507, PubMed:36991122, PubMed:36991125).<ref>PMID:27281216</ref> <ref>PMID:32299851</ref> <ref>PMID:34022140</ref> <ref>PMID:36157507</ref> <ref>PMID:36599845</ref> <ref>PMID:36991122</ref> <ref>PMID:36991125</ref>   Precursor of a pore-forming protein that acts as a downstream mediator of granzyme-mediated cell death and mediates pyroptosis (PubMed:28154144, PubMed:36157507, PubMed:36899106, PubMed:36991122, PubMed:36991125). Following cleavage and activation by granzyme A (GZMA), the N-terminal part binds to membrane inner leaflet lipids, homooligomerizes within the human plasma membrane and forms pores of 10-15 nanometers (nm) of inner diameter, triggering pyroptosis (PubMed:28154144, PubMed:36157507, PubMed:36899106, PubMed:36991122, PubMed:36991125). Recognizes and binds membrane inner leaflet lipids of human cells, such as phosphatidylinositol 4-phosphate, phosphatidylinositol 5-phosphate, bisphosphorylated phosphatidylinositols, such as phosphatidylinositol (4,5)-bisphosphate, and more weakly to phosphatidic acid (PubMed:28154144, PubMed:36157507). Also binds sufatide, a component of the apical membrane of epithelial cells (PubMed:28154144).<ref>PMID:28154144</ref> <ref>PMID:36157507</ref> <ref>PMID:36899106</ref> <ref>PMID:36991122</ref> <ref>PMID:36991125</ref>   Precursor of a pore-forming protein that acts as a downstream mediator of granzyme-mediated cell death and mediates pyroptosis of human cells (PubMed:36899106, PubMed:36991122, PubMed:36991125). Following cleavage and activation by granzyme A (GZMA), the N-terminal part binds to membrane inner leaflet lipids, homooligomerizes within the human plasma membrane and forms pores of 10-15 nanometers (nm) of inner diameter, triggering pyroptosis (PubMed:36899106, PubMed:36991122, PubMed:36991125).<ref>PMID:36899106</ref> <ref>PMID:36991122</ref> <ref>PMID:36991125</ref>   Precursor of a pore-forming protein that acts as a downstream mediator of granzyme-mediated cell death and specifically mediates cell death of Gram-negative bacteria in response to infection (PubMed:34022140). Following cleavage and activation by granzyme A (GZMA), the N-terminal part recognizes and binds phospholipids found on Gram-negative bacterial membranes, such as lipid A and cariolipin, homooligomerizes within the bacterial membranes and forms pores, triggering pyroptosis followed by cell death (PubMed:34022140). In contrast to isoform 4, does not bind to membrane inner leaflet lipids of host human cell, such as phosphatidylinositol 4-phosphate, phosphatidylinositol 5-phosphate, bisphosphorylated phosphatidylinositols, such as phosphatidylinositol (4,5)-bisphosphate (PubMed:34022140).<ref>PMID:34022140</ref>   Not able to trigger pyroptosis.<ref>PMID:36899106</ref> <ref>PMID:36991122</ref> <ref>PMID:36991125</ref>   Not able to trigger pyroptosis.<ref>PMID:36899106</ref> <ref>PMID:36991122</ref> <ref>PMID:36991125</ref> 
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== Publication Abstract from PubMed ==
Cytotoxic lymphocyte-derived granzyme A (GZMA) cleaves GSDMB, a gasdermin-family pore-forming protein(1,2), to trigger target cell pyroptosis(3). GSDMB and the charter gasdermin family member GSDMD(4,5) have been inconsistently reported to be degraded by the Shigella flexneri ubiquitin-ligase virulence factor IpaH7.8 (refs. (6,7)). Whether and how IpaH7.8 targets both gasdermins is undefined, and the pyroptosis function of GSDMB has even been questioned recently(6,8). Here we report the crystal structure of the IpaH7.8-GSDMB complex, which shows how IpaH7.8 recognizes the GSDMB pore-forming domain. We clarify that IpaH7.8 targets human (but not mouse) GSDMD through a similar mechanism. The structure of full-length GSDMB suggests stronger autoinhibition than in other gasdermins(9,10). GSDMB has multiple splicing isoforms that are equally targeted by IpaH7.8 but exhibit contrasting pyroptotic activities. Presence of exon 6 in the isoforms dictates the pore-forming, pyroptotic activity in GSDMB. We determine the cryo-electron microscopy structure of the 27-fold-symmetric GSDMB pore and depict conformational changes that drive pore formation. The structure uncovers an essential role for exon-6-derived elements in pore assembly, explaining pyroptosis deficiency in the non-canonical splicing isoform used in recent studies(6,8). Different cancer cell lines have markedly different isoform compositions, correlating with the onset and extent of pyroptosis following GZMA stimulation. Our study illustrates fine regulation of GSDMB pore-forming activity by pathogenic bacteria and mRNA splicing and defines the underlying structural mechanisms.

Structural mechanisms for regulation of GSDMB pore-forming activity.,Zhong X, Zeng H, Zhou Z, Su Y, Cheng H, Hou Y, She Y, Feng N, Wang J, Shao F, Ding J Nature. 2023 Apr;616(7957):598-605. doi: 10.1038/s41586-023-05872-5. Epub 2023 , Mar 29. PMID:36991125<ref>PMID:36991125</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Cheng H]]
[[Category: Ding J]]
[[Category: Hou YJ]]