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Structure and dynamics of ASC2, a pyrin domain-only protein that regulates inflammatory signaling.

Natarajan A, Ghose R, Hill JM
J Biol Chem 281 31863-75 (2006)
Cited: 39 times
EuropePMC logo PMID: 16905547

Abstract

Pyrin domain (PYD)-containing proteins are key components of pathways that regulate inflammation, apoptosis, and cytokine processing. Their importance is further evidenced by the consequences of mutations in these proteins that give rise to autoimmune and hyperinflammatory syndromes. PYDs, like other members of the death domain (DD) superfamily, are postulated to mediate homotypic interactions that assemble and regulate the activity of signaling complexes. However, PYDs are presently the least well characterized of all four DD subfamilies. Here we report the three-dimensional structure and dynamic properties of ASC2, a PYD-only protein that functions as a modulator of multidomain PYD-containing proteins involved in NF-kappaB and caspase-1 activation. ASC2 adopts a six-helix bundle structure with a prominent loop, comprising 13 amino acid residues, between helices two and three. This loop represents a divergent feature of PYDs from other domains with the DD fold. Detailed analysis of backbone 15N NMR relaxation data using both the Lipari-Szabo model-free and reduced spectral density function formalisms revealed no evidence of contiguous stretches of polypeptide chain with dramatically increased internal motion, except at the extreme N and C termini. Some mobility in the fast, picosecond to nanosecond timescale, was seen in helix 3 and the preceding alpha2-alpha3 loop, in stark contrast to the complete disorder seen in the corresponding region of the NALP1 PYD. Our results suggest that extensive conformational flexibility in helix 3 and the alpha2-alpha3 loop is not a general feature of pyrin domains. Further, a transition from complete disorder to order of the alpha2-alpha3 loop upon binding, as suggested for NALP1, is unlikely to be a common attribute of pyrin domain interactions.

Reviews - 2hm2 mentioned but not cited (2)

  1. Inhibiting the inflammasome: one domain at a time. Dorfleutner A, Chu L, Stehlik C. Immunol Rev 265 205-216 (2015)
  2. Assembly of platforms for signal transduction in the new era: dimerization, helical filament assembly, and beyond. Ha HJ, Chun HL, Park HH. Exp Mol Med 52 356-366 (2020)

Articles - 2hm2 mentioned but not cited (14)

  1. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, Latz E, Fitzgerald KA. Nature 458 514-518 (2009)
  2. Crystal structure of NALP3 protein pyrin domain (PYD) and its implications in inflammasome assembly. Bae JY, Park HH. J Biol Chem 286 39528-39536 (2011)
  3. Structure of the absent in melanoma 2 (AIM2) pyrin domain provides insights into the mechanisms of AIM2 autoinhibition and inflammasome assembly. Jin T, Perry A, Smith P, Jiang J, Xiao TS. J Biol Chem 288 13225-13235 (2013)
  4. Multiple binding sites on the pyrin domain of ASC protein allow self-association and interaction with NLRP3 protein. Vajjhala PR, Mirams RE, Hill JM. J Biol Chem 287 41732-41743 (2012)
  5. Improved AlphaFold modeling with implicit experimental information. Terwilliger TC, Poon BK, Afonine PV, Schlicksup CJ, Croll TI, Millán C, Richardson JS, Read RJ, Adams PD. Nat Methods 19 1376-1382 (2022)
  6. Three-dimensional structure of the NLRP7 pyrin domain: insight into pyrin-pyrin-mediated effector domain signaling in innate immunity. Pinheiro AS, Proell M, Eibl C, Page R, Schwarzenbacher R, Peti W. J Biol Chem 285 27402-27410 (2010)
  7. Mapping of POP1-binding site on pyrin domain of ASC. Srimathi T, Robbins SL, Dubas RL, Chang H, Cheng H, Roder H, Park YC. J Biol Chem 283 15390-15398 (2008)
  8. Structural and functional analysis of the NLRP4 pyrin domain. Eibl C, Grigoriu S, Hessenberger M, Wenger J, Puehringer S, Pinheiro AS, Wagner RN, Proell M, Reed JC, Page R, Diederichs K, Peti W. Biochemistry 51 7330-7341 (2012)
  9. An updated view on the structure and function of PYRIN domains. Chu LH, Gangopadhyay A, Dorfleutner A, Stehlik C. Apoptosis 20 157-173 (2015)
  10. Three-dimensional structure of human NLRP10/PYNOD pyrin domain reveals a homotypic interaction site distinct from its mouse homologue. Su MY, Kuo CI, Chang CF, Chang CI. PLoS One 8 e67843 (2013)
  11. Structures of the NLRP14 pyrin domain reveal a conformational switch mechanism regulating its molecular interactions. Eibl C, Hessenberger M, Wenger J, Brandstetter H. Acta Crystallogr D Biol Crystallogr 70 2007-2018 (2014)
  12. Crystallization and preliminary X-ray crystallographic studies of the PYD domain of human NALP3. Bae JY, Park HH. Acta Crystallogr Sect F Struct Biol Cryst Commun 67 1421-1424 (2011)
  13. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)
  14. Solution NMR structure of VF0530 from Vibrio fischeri reveals a nucleic acid-binding function. Aramini JM, Rossi P, Fischer M, Xiao R, Acton TB, Montelione GT. Proteins 79 2988-2991 (2011)


Reviews citing this publication (12)

  1. An Update on PYRIN Domain-Containing Pattern Recognition Receptors: From Immunity to Pathology. Ratsimandresy RA, Dorfleutner A, Stehlik C. Front Immunol 4 440 (2013)
  2. Assembly and regulation of ASC specks. Hoss F, Rodriguez-Alcazar JF, Latz E. Cell Mol Life Sci 74 1211-1229 (2017)
  3. Pyrin- and CARD-only Proteins as Regulators of NLR Functions. Le HT, Harton JA. Front Immunol 4 275 (2013)
  4. The hierarchical structural architecture of inflammasomes, supramolecular inflammatory machines. Hauenstein AV, Zhang L, Wu H. Curr Opin Struct Biol 31 75-83 (2015)
  5. Structure, interactions and self-assembly of ASC-dependent inflammasomes. de Alba E. Arch Biochem Biophys 670 15-31 (2019)
  6. Immunobiology and structural biology of AIM2 inflammasome. Wang B, Bhattacharya M, Roy S, Tian Y, Yin Q. Mol Aspects Med 76 100869 (2020)
  7. COPs and POPs Patrol Inflammasome Activation. Indramohan M, Stehlik C, Dorfleutner A. J Mol Biol 430 153-173 (2018)
  8. PYRIN domains and their interactions in the apoptosis and inflammation signaling pathway. Park HH. Apoptosis 17 1247-1257 (2012)
  9. Higher-order assemblies in immune signaling: supramolecular complexes and phase separation. Xia S, Chen Z, Shen C, Fu TM. Protein Cell 12 680-694 (2021)
  10. CARD- and pyrin-only proteins regulating inflammasome activation and immunity. Matusiak M, Van Opdenbosch N, Lamkanfi M. Immunol Rev 265 217-230 (2015)
  11. Activation and assembly of the inflammasomes through conserved protein domain families. Jin T, Xiao TS. Apoptosis 20 151-156 (2015)
  12. Steroid Hormone Receptor Coregulators in Endocrine Cancers. Obeid JP, Zafar N, El Hokayem J. IUBMB Life 68 504-515 (2016)

Articles citing this publication (11)

  1. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Bürckstümmer T, Baumann C, Blüml S, Dixit E, Dürnberger G, Jahn H, Planyavsky M, Bilban M, Colinge J, Bennett KL, Superti-Furga G. Nat Immunol 10 266-272 (2009)
  2. The Nod-like receptor (NLR) family: a tale of similarities and differences. Proell M, Riedl SJ, Fritz JH, Rojas AM, Schwarzenbacher R. PLoS One 3 e2119 (2008)
  3. Structure and interdomain dynamics of apoptosis-associated speck-like protein containing a CARD (ASC). de Alba E. J Biol Chem 284 32932-32941 (2009)
  4. ASC Pyrin Domain Self-associates and Binds NLRP3 Protein Using Equivalent Binding Interfaces. Oroz J, Barrera-Vilarmau S, Alfonso C, Rivas G, de Alba E. J Biol Chem 291 19487-19501 (2016)
  5. The NLRP12 pyrin domain: structure, dynamics, and functional insights. Pinheiro AS, Eibl C, Ekman-Vural Z, Schwarzenbacher R, Peti W. J Mol Biol 413 790-803 (2011)
  6. Crystal structure of the F27G AIM2 PYD mutant and similarities of its self-association to DED/DED interactions. Lu A, Kabaleeswaran V, Fu T, Magupalli VG, Wu H. J Mol Biol 426 1420-1427 (2014)
  7. Uncoupling of Pyrin-only protein 2 (POP2)-mediated dual regulation of NF-κB and the inflammasome. Atianand MK, Harton JA. J Biol Chem 286 40536-40547 (2011)
  8. Identification of multifaceted binding modes for pyrin and ASC pyrin domains gives insights into pyrin inflammasome assembly. Vajjhala PR, Kaiser S, Smith SJ, Ong QR, Soh SL, Stacey KJ, Hill JM. J Biol Chem 289 23504-23519 (2014)
  9. Intrinsic flexibility of NLRP pyrin domains is a key factor in their conformational dynamics, fold stability, and dimerization. Huber RG, Eibl C, Fuchs JE. Protein Sci 24 174-181 (2015)
  10. A molecular dynamics study of the ASC and NALP1 pyrin domains at neutral and low pH. Gattin Z, van Gunsteren WF. Chembiochem 9 923-933 (2008)
  11. Natural and engineered inflammasome adapter proteins reveal optimum linker length for self-assembly. Diaz-Parga P, Gould A, de Alba E. J Biol Chem 298 102501 (2022)


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