6kmt

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P32 of caspase-11 mutant C254AP32 of caspase-11 mutant C254A

Structural highlights

6kmt is a 4 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.6Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CASP4_MOUSE Proinflammatory caspase (PubMed:8702803, PubMed:9038361, PubMed:25119034). Essential effector of NLRP3 inflammasome-dependent CASP1 activation and IL1B and IL18 secretion in response to non-canonical activators, such as UVB radiation, cholera enterotoxin subunit B and cytosolic LPS, as well as infection with Gram-negative bacteria (PubMed:22002608). Independently of NLRP3 inflammasome and CASP1, promotes pyroptosis, through GSDMD cleavage and activation, and IL1A, IL18 and HMGB1 release in response to non-canonical inflammasome activators (PubMed:22002608, PubMed:26320999, PubMed:26375003). Plays a crucial role in the restriction of Salmonella typhimurium replication in colonic epithelial cells during infection. In later stages of the infection (>3 days post infection), LPS from cytosolic Salmonella triggers CASP4 activation, which ultimately results in the pyroptosis of the infected cells and their extrusion into the gut lumen, as well as in IL18 secretion. Pyroptosis limits bacterial replication, while cytokine secretion promotes the recruitment and activation of immune cells and triggers mucosal inflammation (PubMed:25121752). Involved in LPS-induced IL6 secretion; this activity may not require caspase enzymatic activity (By similarity). Involved in cell death induced by endoplasmic reticulum stress (By similarity). Activated by direct binding to LPS without the need of an upstream sensor (PubMed:25119034). Does not directly process IL1B (PubMed:8702803, PubMed:9038361). During non-canonical inflammasome activation, cuts CGAS and may play a role in the regulation of antiviral innate immune activation (PubMed:28314590).[UniProtKB:P49662][1] [2] [3] [4] [5] [6] [7] [8]

Publication Abstract from PubMed

The pyroptosis execution protein GSDMD is cleaved by inflammasome-activated caspase-1 and LPS-activated caspase-11/4/5. The cleavage unmasks the pore-forming domain from GSDMD-C-terminal domain. How the caspases recognize GSDMD and its connection with caspase activation are unknown. Here, we show site-specific caspase-4/11 autoprocessing, generating a p10 product, is required and sufficient for cleaving GSDMD and inducing pyroptosis. The p10-form autoprocessed caspase-4/11 binds the GSDMD-C domain with a high affinity. Structural comparison of autoprocessed and unprocessed capase-11 identifies a beta sheet induced by the autoprocessing. In caspase-4/11-GSDMD-C complex crystal structures, the beta sheet organizes a hydrophobic GSDMD-binding interface that is only possible for p10-form caspase-4/11. The binding promotes dimerization-mediated caspase activation, rendering a cleavage independently of the cleavage-site tetrapeptide sequence. Crystal structure of caspase-1-GSDMD-C complex shows a similar GSDMD-recognition mode. Our study reveals an unprecedented substrate-targeting mechanism for caspases. The hydrophobic interface suggests an additional space for developing inhibitors specific for pyroptotic caspases.

Structural Mechanism for GSDMD Targeting by Autoprocessed Caspases in Pyroptosis.,Wang K, Sun Q, Zhong X, Zeng M, Zeng H, Shi X, Li Z, Wang Y, Zhao Q, Shao F, Ding J Cell. 2020 Mar 5;180(5):941-955.e20. doi: 10.1016/j.cell.2020.02.002. Epub 2020, Feb 27. PMID:32109412[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Kayagaki N, Warming S, Lamkanfi M, Vande Walle L, Louie S, Dong J, Newton K, Qu Y, Liu J, Heldens S, Zhang J, Lee WP, Roose-Girma M, Dixit VM. Non-canonical inflammasome activation targets caspase-11. Nature. 2011 Oct 16;479(7371):117-21. doi: 10.1038/nature10558. PMID:22002608 doi:http://dx.doi.org/10.1038/nature10558
  2. ↑ Shi J, Zhao Y, Wang Y, Gao W, Ding J, Li P, Hu L, Shao F. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature. 2014 Oct 9;514(7521):187-92. doi: 10.1038/nature13683. Epub 2014 Aug 6. PMID:25119034 doi:http://dx.doi.org/10.1038/nature13683
  3. ↑ Knodler LA, Crowley SM, Sham HP, Yang H, Wrande M, Ma C, Ernst RK, Steele-Mortimer O, Celli J, Vallance BA. Noncanonical inflammasome activation of caspase-4/caspase-11 mediates epithelial defenses against enteric bacterial pathogens. Cell Host Microbe. 2014 Aug 13;16(2):249-256. doi: 10.1016/j.chom.2014.07.002. PMID:25121752 doi:http://dx.doi.org/10.1016/j.chom.2014.07.002
  4. ↑ Aachoui Y, Kajiwara Y, Leaf IA, Mao D, Ting JP, Coers J, Aderem A, Buxbaum JD, Miao EA. Canonical Inflammasomes Drive IFN-gamma to Prime Caspase-11 in Defense against a Cytosol-Invasive Bacterium. Cell Host Microbe. 2015 Sep 9;18(3):320-32. doi: 10.1016/j.chom.2015.07.016. Epub, 2015 Aug 27. PMID:26320999 doi:http://dx.doi.org/10.1016/j.chom.2015.07.016
  5. ↑ 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
  6. ↑ Wang Y, Ning X, Gao P, Wu S, Sha M, Lv M, Zhou X, Gao J, Fang R, Meng G, Su X, Jiang Z. Inflammasome Activation Triggers Caspase-1-Mediated Cleavage of cGAS to Regulate Responses to DNA Virus Infection. Immunity. 2017 Mar 21;46(3):393-404. doi: 10.1016/j.immuni.2017.02.011. Epub 2017, Mar 14. PMID:28314590 doi:http://dx.doi.org/10.1016/j.immuni.2017.02.011
  7. ↑ Wang S, Miura M, Jung Y, Zhu H, Gagliardini V, Shi L, Greenberg AH, Yuan J. Identification and characterization of Ich-3, a member of the interleukin-1beta converting enzyme (ICE)/Ced-3 family and an upstream regulator of ICE. J Biol Chem. 1996 Aug 23;271(34):20580-7. PMID:8702803
  8. ↑ Van de Craen M, Vandenabeele P, Declercq W, Van den Brande I, Van Loo G, Molemans F, Schotte P, Van Criekinge W, Beyaert R, Fiers W. Characterization of seven murine caspase family members. FEBS Lett. 1997 Feb 10;403(1):61-9. PMID:9038361
  9. ↑ Wang K, Sun Q, Zhong X, Zeng M, Zeng H, Shi X, Li Z, Wang Y, Zhao Q, Shao F, Ding J. Structural Mechanism for GSDMD Targeting by Autoprocessed Caspases in Pyroptosis. Cell. 2020 Mar 5;180(5):941-955.e20. doi: 10.1016/j.cell.2020.02.002. Epub 2020, Feb 27. PMID:32109412 doi:http://dx.doi.org/10.1016/j.cell.2020.02.002

6kmt, resolution 2.60Å

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