Proteopedia

7e5b

Crystal structure of ASC PYD Domain and Rb-B7Crystal structure of ASC PYD Domain and Rb-B7

Structural highlights

7e5b is a 4 chain structure with sequence from Cyclostomata and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.29Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ASC_HUMAN Functions as key mediator in apoptosis and inflammation. Promotes caspase-mediated apoptosis involving predominantly caspase-8 and also caspase-9 in a probable cell type-specific manner. Involved in activation of the mitochondrial apoptotic pathway, promotes caspase-8-dependent proteolytic maturation of BID independently of FADD in certain cell types and also mediates mitochondrial translocation of BAX and activates BAX-dependent apoptosis coupled to activation of caspase-9, -2 and -3. Involved in macrophage pyroptosis, a caspase-1-dependent inflammatory form of cell death and is the major constituent of the ASC pyroptosome which forms upon potassium depletion and rapidly recruits and activates caspase-1. In innate immune response believed to act as an integral adapter in the assembly of the inflammasome which activates caspase-1 leading to processing and secretion of proinflammatory cytokines. The function as activating adapter in different types of inflammasomes is mediated by the DAPIN and CARD domains and their homotypic interactions. Required for recruitment of caspase-1 to inflammasomes containing certain pattern recognition receptors, such as NLRP2, NLRP3, AIM2 and probably IFI16. In the NLRP1 and NLRC4 inflammasomes seems not be required but facilitates the processing of procaspase-1. In cooperation with NOD2 involved in an inflammasome activated by bacterial muramyl dipeptide leading to caspase-1 activation. May be involved in DDX58-triggered proinflammatory responses and inflammasome activation. Isoform 2 may have a regulating effect on the function as inflammasome adapter. Isoform 3 seems to inhibit inflammasome-mediated maturation of interleukin-1 beta. In collaboration with AIM2 which detects cytosolic double-stranded DNA may also be involved in a caspase-1-independent cell death that involves caspase-8. In adaptive immunity may be involved in maturation of dendritic cells to stimulate T-cell immunity and in cytoskeletal rearrangements coupled to chemotaxis and antigen uptake may be involved in post-transcriptional regulation of the guanine nucleotide exchange factor DOCK2; the latter function is proposed to involve the nuclear form. Also involved in transcriptional activation of cytokines and chemokines independent of the inflammasome; this function may involve AP-1, NF-kappa-B, MAPK and caspase-8 signaling pathways. For regulation of NF-kappa-B activating and inhibiting functions have been reported. Modulates NF-kappa-B induction at the level of the IKK complex by inhibiting kinase activity of CHUK and IKBK. Proposed to compete with RIPK2 for association with CASP1 thereby down-regulating CASP1-mediated RIPK2-dependent NF-kappa-B activation and activating interleukin-1 beta processing.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19]

Publication Abstract from PubMed

Inflammasomes are multi-protein complexes and play a crucial role in host defense against pathogens. Downstream inflammatory responses through inflammasomes are known to be related to the oligomerization degree of ASC specks, but the detailed mechanism still remains unexplored. Here, we demonstrate that oligomerization degrees of ASC specks regulate the caspase-1 activation in the extracellular space. A protein binder specific for a pyrin domain (PYD) of ASC (ASC(PYD)) was developed, and structural analysis revealed that the protein binder effectively inhibits the interaction between PYDs, disassembling ASC specks into low oligomeric states. ASC specks with a low oligomerization degree were shown to enhance the activation of caspase-1 by recruiting and processing more premature caspase-1 through interactions between CARD of caspase-1 (caspase-1(CARD)) and CARD of ASC (ASC(CARD)). These findings can provide insight into controlling the inflammasome-mediated inflammatory process as well as the development of inflammasome-targeting drugs.

Oligomeric states of ASC specks regulate inflammatory responses by inflammasome in the extracellular space.,Yu TG, Cha JS, Kim G, Sohn YK, Yoo Y, Kim U, Song JJ, Cho HS, Kim HS Cell Death Discov. 2023 Apr 29;9(1):142. doi: 10.1038/s41420-023-01438-6. PMID:37120628[20]

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

References

  1. ↑ Matsushita K, Takeoka M, Sagara J, Itano N, Kurose Y, Nakamura A, Taniguchi S. A splice variant of ASC regulates IL-1beta release and aggregates differently from intact ASC. Mediators Inflamm. 2009;2009:287387. doi: 10.1155/2009/287387. Epub 2009 Sep 15. PMID:19759850 doi:http://dx.doi.org/10.1155/2009/287387
  2. ↑ McConnell BB, Vertino PM. Activation of a caspase-9-mediated apoptotic pathway by subcellular redistribution of the novel caspase recruitment domain protein TMS1. Cancer Res. 2000 Nov 15;60(22):6243-7. PMID:11103777
  3. ↑ Stehlik C, Fiorentino L, Dorfleutner A, Bruey JM, Ariza EM, Sagara J, Reed JC. The PAAD/PYRIN-family protein ASC is a dual regulator of a conserved step in nuclear factor kappaB activation pathways. J Exp Med. 2002 Dec 16;196(12):1605-15. PMID:12486103
  4. ↑ Masumoto J, Dowds TA, Schaner P, Chen FF, Ogura Y, Li M, Zhu L, Katsuyama T, Sagara J, Taniguchi S, Gumucio DL, Nunez G, Inohara N. ASC is an activating adaptor for NF-kappa B and caspase-8-dependent apoptosis. Biochem Biophys Res Commun. 2003 Mar 28;303(1):69-73. PMID:12646168
  5. ↑ Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity. 2004 Mar;20(3):319-25. PMID:15030775
  6. ↑ Ohtsuka T, Ryu H, Minamishima YA, Macip S, Sagara J, Nakayama KI, Aaronson SA, Lee SW. ASC is a Bax adaptor and regulates the p53-Bax mitochondrial apoptosis pathway. Nat Cell Biol. 2004 Feb;6(2):121-8. Epub 2004 Jan 18. PMID:14730312 doi:http://dx.doi.org/10.1038/ncb1087
  7. ↑ Sarkar A, Duncan M, Hart J, Hertlein E, Guttridge DC, Wewers MD. ASC directs NF-kappaB activation by regulating receptor interacting protein-2 (RIP2) caspase-1 interactions. J Immunol. 2006 Apr 15;176(8):4979-86. PMID:16585594
  8. ↑ Taxman DJ, Zhang J, Champagne C, Bergstralh DT, Iocca HA, Lich JD, Ting JP. Cutting edge: ASC mediates the induction of multiple cytokines by Porphyromonas gingivalis via caspase-1-dependent and -independent pathways. J Immunol. 2006 Oct 1;177(7):4252-6. PMID:16982856
  9. ↑ Fernandes-Alnemri T, Wu J, Yu JW, Datta P, Miller B, Jankowski W, Rosenberg S, Zhang J, Alnemri ES. The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation. Cell Death Differ. 2007 Sep;14(9):1590-604. Epub 2007 Jun 29. PMID:17599095 doi:http://dx.doi.org/10.1038/sj.cdd.4402194
  10. ↑ Faustin B, Lartigue L, Bruey JM, Luciano F, Sergienko E, Bailly-Maitre B, Volkmann N, Hanein D, Rouiller I, Reed JC. Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol Cell. 2007 Mar 9;25(5):713-24. PMID:17349957 doi:10.1016/j.molcel.2007.01.032
  11. ↑ Hasegawa M, Kawase K, Inohara N, Imamura R, Yeh WC, Kinoshita T, Suda T. Mechanism of ASC-mediated apoptosis: bid-dependent apoptosis in type II cells. Oncogene. 2007 Mar 15;26(12):1748-56. Epub 2006 Sep 11. PMID:16964285 doi:http://dx.doi.org/10.1038/sj.onc.1209965
  12. ↑ Bryan NB, Dorfleutner A, Rojanasakul Y, Stehlik C. Activation of inflammasomes requires intracellular redistribution of the apoptotic speck-like protein containing a caspase recruitment domain. J Immunol. 2009 Mar 1;182(5):3173-82. doi: 10.4049/jimmunol.0802367. PMID:19234215 doi:http://dx.doi.org/10.4049/jimmunol.0802367
  13. ↑ Hasegawa M, Imamura R, Motani K, Nishiuchi T, Matsumoto N, Kinoshita T, Suda T. Mechanism and repertoire of ASC-mediated gene expression. J Immunol. 2009 Jun 15;182(12):7655-62. doi: 10.4049/jimmunol.0800448. PMID:19494289 doi:http://dx.doi.org/10.4049/jimmunol.0800448
  14. ↑ Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature. 2009 Mar 26;458(7237):509-13. doi: 10.1038/nature07710. Epub 2009 Jan 21. PMID:19158676 doi:10.1038/nature07710
  15. ↑ Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, Latz E, Fitzgerald KA. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature. 2009 Mar 26;458(7237):514-8. doi: 10.1038/nature07725. Epub 2009 Jan 21. PMID:19158675 doi:10.1038/nature07725
  16. ↑ Bryan NB, Dorfleutner A, Kramer SJ, Yun C, Rojanasakul Y, Stehlik C. Differential splicing of the apoptosis-associated speck like protein containing a caspase recruitment domain (ASC) regulates inflammasomes. J Inflamm (Lond). 2010 May 18;7:23. doi: 10.1186/1476-9255-7-23. PMID:20482797 doi:http://dx.doi.org/10.1186/1476-9255-7-23
  17. ↑ Taxman DJ, Holley-Guthrie EA, Huang MT, Moore CB, Bergstralh DT, Allen IC, Lei Y, Gris D, Ting JP. The NLR adaptor ASC/PYCARD regulates DUSP10, mitogen-activated protein kinase (MAPK), and chemokine induction independent of the inflammasome. J Biol Chem. 2011 Jun 3;286(22):19605-16. doi: 10.1074/jbc.M111.221077. Epub 2011, Apr 12. PMID:21487011 doi:http://dx.doi.org/10.1074/jbc.M111.221077
  18. ↑ Guo X, Dhodapkar KM. Central and overlapping role of Cathepsin B and inflammasome adaptor ASC in antigen presenting function of human dendritic cells. Hum Immunol. 2012 Sep;73(9):871-8. doi: 10.1016/j.humimm.2012.06.008. Epub 2012, Jun 22. PMID:22732093 doi:http://dx.doi.org/10.1016/j.humimm.2012.06.008
  19. ↑ Liepinsh E, Barbals R, Dahl E, Sharipo A, Staub E, Otting G. The death-domain fold of the ASC PYRIN domain, presenting a basis for PYRIN/PYRIN recognition. J Mol Biol. 2003 Oct 3;332(5):1155-63. PMID:14499617
  20. ↑ Yu TG, Cha JS, Kim G, Sohn YK, Yoo Y, Kim U, Song JJ, Cho HS, Kim HS. Oligomeric states of ASC specks regulate inflammatory responses by inflammasome in the extracellular space. Cell Death Discov. 2023 Apr 29;9(1):142. PMID:37120628 doi:10.1038/s41420-023-01438-6

7e5b, resolution 2.29Å

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