5tib: Difference between revisions
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==Gasdermin-B C-terminal domain containing the polymorphism residues Arg299:Ser306 fused to maltose binding protein== | ==Gasdermin-B C-terminal domain containing the polymorphism residues Arg299:Ser306 fused to maltose binding protein== | ||
<StructureSection load='5tib' size='340' side='right' caption='[[5tib]], [[Resolution|resolution]] 2.60Å' scene=''> | <StructureSection load='5tib' size='340' side='right'caption='[[5tib]], [[Resolution|resolution]] 2.60Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5tib]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TIB OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[5tib]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TIB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TIB FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand= | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6Å</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PRD_900001:alpha-maltose'>PRD_900001</scene></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=5tib FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tib OCA], [https://pdbe.org/5tib PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tib RCSB], [https://www.ebi.ac.uk/pdbsum/5tib PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tib ProSAT]</span></td></tr> | |||
</table> | </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). The different isoforms recognize and bind different phospholipids on membranes, promoting cell death of different target cells (PubMed:34022140, PubMed:36157507).<ref>PMID:27281216</ref> <ref>PMID:32299851</ref> <ref>PMID:34022140</ref> <ref>PMID:36157507</ref> Precursor of a pore-forming protein that acts as a downstream mediator of granzyme-mediated cell death and mediates pyroptosis of host human cells (PubMed:28154144, PubMed:36157507). 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). 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> 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 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> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The exact function of human gasdermin-B (GSDMB), which regulates differentiation and growth of epithelial cells, is yet to be elucidated. In human epidermal growth factor receptor 2 (HER2)-positive breast cancer, GSDMB gene amplification and protein overexpression indicate a poor response to HER2-targeted therapy. Genome-wide association studies revealed a correlation between GSDMB SNPs and an increased susceptibility to Crohn's disease, ulcerative colitis, and asthma. The N- and C-terminal domains of all gasdermins possess lipid-binding and regulatory activities, respectively. Inflammatory caspases cleave gasdermin-D in the interdomain linker but not GSDMB. The cleaved N-terminal domain binds phosphoinositides and cardiolipin, forms membrane-disrupting pores, and executes pyroptosis. We show that both full-length GSDMB and the N-terminal domain bind to nitrocellulose membranes immobilized with phosphoinositides or sulfatide, but not with cardiolipin. In addition, the GSDMB N-terminal domain binds liposomes containing sulfatide. The crystal structure of the GSDMB C-terminal domain reveals the structural impact of the amino acids encoded by SNPs that are linked to asthma and inflammatory bowel disease (IBD). A loop that carries the polymorphism amino acids corresponding to healthy individuals (Gly299:Pro306) exhibits high conformational flexibility, whereas the loop carrying amino acids found in individuals with increased disease risk (Arg299:Ser306) exhibits a well-defined conformation and higher positive surface charge. Apoptotic executioner caspase-3, -6, and -7, but not the inflammatory caspases, cleave GSDMB at 88DNVD91 within the N-terminal domain. Selective sulfatide binding may indicate possible function for GSDMB in the cellular sulfatide transport. | |||
Gene polymorphism linked to increased asthma and IBD risk alters gasdermin-B structure, a sulfatide and phosphoinositide binding protein.,Chao KL, Kulakova L, Herzberg O Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):E1128-E1137. doi:, 10.1073/pnas.1616783114. Epub 2017 Feb 1. PMID:28154144<ref>PMID:28154144</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5tib" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Gasdermin 3D structures|Gasdermin 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Escherichia coli]] | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Chao K]] | ||
[[Category: | [[Category: Herzberg O]] | ||