Directionality of PYD filament growth determined by the transition of NLRP3 nucleation seeds to ASC elongation. Academic Article uri icon

Overview

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 NLRP3PYD 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 NLRP3PYD 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.

publication date

  • May 13, 2022

Identity

PubMed Central ID

  • PMC9106292

Scopus Document Identifier

  • 85130071970

Digital Object Identifier (DOI)

  • 10.1101/2021.09.17.460822

PubMed ID

  • 35559676

Additional Document Info

volume

  • 8

issue

  • 19