Universität zu Köln

Hochheiser, Inga, V, Behrmann, Heide, Hagelueken, Gregor ORCID: 0000-0001-8781-5664, Rodriguez-Alcazar, Juan F., Kopp, Anja ORCID: 0000-0001-5484-7109, Latz, Eicke, Behrmann, Elmar ORCID: 0000-0001-6794-3669 and Geyer, Matthias ORCID: 0000-0002-7718-5002 (2022). Directionality of PYD filament growth determined by the transition of NLRP3 nucleation seeds to ASC elongation. Sci. Adv., 8 (19). WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE. ISSN 2375-2548

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Abstract

Inflammasomes sense intrinsic and extrinsic danger signals to trigger inflammatory responses and pyroptotic cell death. Homotypic pyrin domain (PYD) interactions of inflammasome forming nucleotide-binding oligomerization domain (NOD)-like receptors with the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) mediate oligomerization into filamentous assemblies. We describe the cryo-electron microscopy (cryo-EM) structure of the human NLRP3(PYD) filament and identify a pattern of highly polar interface residues that form the homomeric interactions leading to characteristic filament ends designated as A- and B-ends. Coupling a titration polymerization assay to cryo-EM, we demonstrate that ASC adaptor protein elongation on NLRP3(PYD) nucleation seeds is unidirectional, associating exclusively to the B-end of the filament. Notably, NLRP3 and ASC PYD filaments exhibit the same symmetry in rotation and axial rise per subunit, allowing a continuous transition between NLRP3 and ASC. Integrating the directionality of filament growth, we present a molecular model of the ASC speck consisting of active NLRP3, ASC, and Caspase-1 proteins.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hochheiser, Inga, V UNSPECIFIED UNSPECIFIED UNSPECIFIED Behrmann, Heide UNSPECIFIED UNSPECIFIED UNSPECIFIED Hagelueken, Gregor UNSPECIFIED orcid.org/0000-0001-8781-5664 UNSPECIFIED Rodriguez-Alcazar, Juan F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kopp, Anja UNSPECIFIED orcid.org/0000-0001-5484-7109 UNSPECIFIED Latz, Eicke UNSPECIFIED UNSPECIFIED UNSPECIFIED Behrmann, Elmar UNSPECIFIED orcid.org/0000-0001-6794-3669 UNSPECIFIED Geyer, Matthias UNSPECIFIED orcid.org/0000-0002-7718-5002 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-674184
DOI:	10.1126/sciadv.abn7583
Journal or Publication Title:	Sci. Adv.
Volume:	8
Number:	19
Date:	2022
Publisher:	AMER ASSOC ADVANCEMENT SCIENCE
Place of Publication:	WASHINGTON
ISSN:	2375-2548
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PYRIN DOMAIN; INFLAMMASOME ACTIVATION; PATTERN-RECOGNITION; CRYSTAL-STRUCTURE; ADAPTER ASC; MECHANISM; MUTATION; RECEPTORS; APOPTOSIS; MAGNESIUM Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/67418