7PZD

Cryo-EM structure of the NLRP3 PYD filament

Summary for 7PZD

• Entry DOI: 10.2210/pdb7pzd/pdb
• EMDB information: 13727
• Descriptor: NACHT, LRR and PYD domains-containing protein 3 (1 entity in total)
• Functional Keywords: nlrp3, pyrin domain, filament, immune system
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 18
• Total formula weight: 224752.37

Authors

Hochheiser, I.V.,Hagelueken, G.,Behrmann, H.,Behrmann, E.,Geyer, M. (deposition date: 2021-10-12, release date: 2022-04-20, Last modification date: 2024-07-17)

Primary citation

Hochheiser, I.V.,Behrmann, H.,Hagelueken, G.,Rodriguez-Alcazar, J.F.,Kopp, A.,Latz, E.,Behrmann, E.,Geyer, M.
Directionality of PYD filament growth determined by the transition of NLRP3 nucleation seeds to ASC elongation.
Sci Adv, 8:eabn7583-eabn7583, 2022

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-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.

PubMed: 35559676
DOI: 10.1126/sciadv.abn7583

Experimental method

ELECTRON MICROSCOPY (3.6 Å)