| Structural highlights
Function
[GSDMD_MOUSE] 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:26611636, PubMed:26375259, PubMed:26375003, PubMed:27418190, PubMed:27385778, PubMed:27383986). After cleavage, moves to the plasma membrane where it strongly binds to membrane 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)-trisphosphate, and more weakly to phosphatidic acid and phosphatidylserine. Homooligomerizes within the membrane and forms pores of 10 - 15 nanometers (nm) of inner diameter, allowing the release of mature IL1B and triggering pyroptosis. 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. Under cell culture conditions, also active against intracellular bacteria, such as Listeria monocytogenes. Strongly binds to bacterial and mitochondrial lipids, including cardiolipin. Does not bind to phosphatidylethanolamine or phosphatidylcholine (PubMed:27383986).[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Gasdermin D (GSDMD) is an effector molecule for pyroptosis downstream of canonical and noncanonical inflammasome signaling pathways. Cleavage of GSDMD by inflammatory caspases triggers the oligomerization and lipid binding by its N-terminal domain, which assembles membrane pores, whereas its C-terminal domain binds the N-terminal domain to inhibit pyroptosis. Despite recent progress in our understanding of the structure and function of the murine gasdermin A3 (mGSDMA3), the molecular mechanisms of GSDMD activation and regulation remain poorly characterized. Here, we report the crystal structures of the full-length murine and human GSDMDs, which reveal the architecture of the GSDMD N-terminal domains and demonstrate distinct and common features of autoinhibition among gasdermin family members utilizing their beta1-beta2 loops. Disruption of the intramolecular domain interface enhanced pyroptosis, whereas mutations at the predicted lipid-binding or oligomerization surface reduced cytolysis. Our study provides a framework for understanding the autoinhibition, lipid binding, and oligomerization of GSDMD by using overlapping interfaces.
Crystal Structures of the Full-Length Murine and Human Gasdermin D Reveal Mechanisms of Autoinhibition, Lipid Binding, and Oligomerization.,Liu Z, Wang C, Yang J, Zhou B, Yang R, Ramachandran R, Abbott DW, Xiao TS Immunity. 2019 May 8. pii: S1074-7613(19)30197-9. doi:, 10.1016/j.immuni.2019.04.017. PMID:31097341[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, Zhuang Y, Cai T, Wang F, Shao F. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015 Oct 29;526(7575):660-5. doi: 10.1038/nature15514. Epub 2015 Sep 16. PMID:26375003 doi:http://dx.doi.org/10.1038/nature15514
- ↑ Kayagaki N, Stowe IB, Lee BL, O'Rourke K, Anderson K, Warming S, Cuellar T, Haley B, Roose-Girma M, Phung QT, Liu PS, Lill JR, Li H, Wu J, Kummerfeld S, Zhang J, Lee WP, Snipas SJ, Salvesen GS, Morris LX, Fitzgerald L, Zhang Y, Bertram EM, Goodnow CC, Dixit VM. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature. 2015 Oct 29;526(7575):666-71. doi: 10.1038/nature15541. Epub 2015 Sep 16. PMID:26375259 doi:http://dx.doi.org/10.1038/nature15541
- ↑ He WT, Wan H, Hu L, Chen P, Wang X, Huang Z, Yang ZH, Zhong CQ, Han J. Gasdermin D is an executor of pyroptosis and required for interleukin-1beta secretion. Cell Res. 2015 Dec;25(12):1285-98. doi: 10.1038/cr.2015.139. Epub 2015 Nov 27. PMID:26611636 doi:http://dx.doi.org/10.1038/cr.2015.139
- ↑ Liu X, Zhang Z, Ruan J, Pan Y, Magupalli VG, Wu H, Lieberman J. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature. 2016 Jul 7;535(7610):153-8. doi: 10.1038/nature18629. PMID:27383986 doi:http://dx.doi.org/10.1038/nature18629
- ↑ Russo HM, Rathkey J, Boyd-Tressler A, Katsnelson MA, Abbott DW, Dubyak GR. Active Caspase-1 Induces Plasma Membrane Pores That Precede Pyroptotic Lysis and Are Blocked by Lanthanides. J Immunol. 2016 Aug 15;197(4):1353-67. doi: 10.4049/jimmunol.1600699. Epub 2016, Jul 6. PMID:27385778 doi:http://dx.doi.org/10.4049/jimmunol.1600699
- ↑ Sborgi L, Ruhl S, Mulvihill E, Pipercevic J, Heilig R, Stahlberg H, Farady CJ, Muller DJ, Broz P, Hiller S. GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. EMBO J. 2016 Aug 15;35(16):1766-78. doi: 10.15252/embj.201694696. Epub 2016 Jul, 14. PMID:27418190 doi:http://dx.doi.org/10.15252/embj.201694696
- ↑ Liu Z, Wang C, Yang J, Zhou B, Yang R, Ramachandran R, Abbott DW, Xiao TS. Crystal Structures of the Full-Length Murine and Human Gasdermin D Reveal Mechanisms of Autoinhibition, Lipid Binding, and Oligomerization. Immunity. 2019 May 8. pii: S1074-7613(19)30197-9. doi:, 10.1016/j.immuni.2019.04.017. PMID:31097341 doi:http://dx.doi.org/10.1016/j.immuni.2019.04.017
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