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
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: |
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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 | ||||||||||||||||||||||||||||||||||||
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URI: | http://kups.ub.uni-koeln.de/id/eprint/67418 |
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