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-Structure paper
Title | Directionality of PYD filament growth determined by the transition of NLRP3 nucleation seeds to ASC elongation. |
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Journal, issue, pages | Sci Adv, Vol. 8, Issue 19, Page eabn7583, Year 2022 |
Publish date | May 13, 2022 |
Authors | Inga V Hochheiser / Heide Behrmann / Gregor Hagelueken / Juan F Rodríguez-Alcázar / Anja Kopp / Eicke Latz / Elmar Behrmann / Matthias Geyer / |
PubMed 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- ...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 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 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. |
External links | Sci Adv / PubMed:35559676 / PubMed Central |
Methods | EM (helical sym.) |
Resolution | 3.6 Å |
Structure data | EMDB-13727, PDB-7pzd: |
Source |
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Keywords | IMMUNE SYSTEM / NLRP3 / Pyrin domain / filament |