6kn0

From Proteopedia

(Difference between revisions)

Revision as of 10:33, 27 March 2020

caspase-1 P20/P10 C285A in complex with human GSDMD-C domain

Structural highlights

6kn0 is a 6 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Related:	6kmu
Gene:	CASP1, IL1BC, IL1BCE (HUMAN), GSDMD, DFNA5L, GSDMDC1, FKSG10 (HUMAN)
Activity:	Caspase-1, with EC number 3.4.22.36
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[CASP1_HUMAN] Thiol protease that cleaves IL-1 beta between an Asp and an Ala, releasing the mature cytokine which is involved in a variety of inflammatory processes. Important for defense against pathogens. Cleaves and activates sterol regulatory element binding proteins (SREBPs). Can also promote apoptosis.^[1] ^[2] [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]^[3] ^[4] ^[5] ^[6]

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^[7]

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

References

↑ Alnemri ES, Fernandes-Alnemri T, Litwack G. Cloning and expression of four novel isoforms of human interleukin-1 beta converting enzyme with different apoptotic activities. J Biol Chem. 1995 Mar 3;270(9):4312-7. PMID:7876192
↑ Feng Q, Li P, Leung PC, Auersperg N. Caspase-1zeta, a new splice variant of the caspase-1 gene. Genomics. 2004 Sep;84(3):587-91. PMID:15498465 doi:http://dx.doi.org/S0888-7543(04)00161-2
↑ 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
↑ Ding J, Wang K, Liu W, She Y, Sun Q, Shi J, Sun H, Wang DC, Shao F. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature. 2016 Jul 7;535(7610):111-6. PMID:27281216 doi:http://dx.doi.org/10.1038/nature18590
↑ 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
↑ 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

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6kn0"

@@ Line 3: / Line 3: @@
 <StructureSection load='6kn0' size='340' side='right'caption='[[6kn0]], [[Resolution|resolution]] 2.79&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6kn0]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KN0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6KN0 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6kn0]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KN0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6KN0 FirstGlance]. <br>
 </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6kmu|6kmu]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CASP1, IL1BC, IL1BCE ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), GSDMD, DFNA5L, GSDMDC1, FKSG10 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Caspase-1 Caspase-1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.36 3.4.22.36] </span></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6kn0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6kn0 OCA], [http://pdbe.org/6kn0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6kn0 RCSB], [http://www.ebi.ac.uk/pdbsum/6kn0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6kn0 ProSAT]</span></td></tr>
@@ Line 24: / Line 25: @@
 </StructureSection>
 [[Category: Caspase-1]]
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Ding, J]]

6kn0

From Proteopedia

Revision as of 10:33, 27 March 2020

caspase-1 P20/P10 C285A in complex with human GSDMD-C domain

Structural highlights

Function

Publication Abstract from PubMed

References

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