9WZD

R125E-ASC PYD filament

Summary for 9WZD

• Entry DOI: 10.2210/pdb9wzd/pdb
• EMDB information: 66391
• Descriptor: Apoptosis-associated speck-like protein containing a CARD (1 entity in total)
• Functional Keywords: filament, pyd, card, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 14
• Total formula weight: 302731.81

Authors

Xue, D.,Ni, F.,Liu, S.,Yan, H.,Luo, Z.,Fu, G.,Wang, Q.,Ma, J. (deposition date: 2025-09-29, release date: 2025-12-10)

Primary citation

Xue, D.,Ni, F.,Liu, S.,Yan, H.,Luo, Z.,Fu, G.,Wang, Q.,Ma, J.
Atomic mechanisms of full-length ASC-mediated inflammasome assembly.
Nat Commun, 16:10564-10564, 2025

PubMed Abstract: ASC (Apoptosis-associated Speck-like protein containing a CARD) is a key adaptor protein that assembles inflammasomes by linking sensors such as NLRP3 to effectors like Caspase-1 via its PYD and CARD Death Domains. Due to ASC's propensity to self-aggregate, most high-resolution structural studies focused on isolated PYD or CARD domains, leaving the atomic basis of full-length ASC assembly unknown. Here we determine atomic-resolution cryo-EM structures of PYD and CARD filaments from full-length ASC, revealing characteristic multitrack bundles composed of alternating ASC and ASC filaments that expose multiple interfaces for flexible assembly and efficient signaling. We further show that Caspase-1 filaments nucleate specifically from the B-end of ASC filaments, and that the interdomain linker modulates bundle formation. The ASC isoform ASCb, with a four-residue linker, adopts a distinct architecture, correlating with reduced Caspase-1 activation efficiency. In ASC THP-1 cells, only wild-type ASC, not interface-disrupting mutants, restored ASC speck formation and Caspase-1 activation, underscoring the requirement for intact multitrack bundles. Cryo-electron tomography captures snapshots of higher-order inflammasome structures. These findings collectively define the structural and functional principles by which ASC organizes inflammasomes to amplify immune signaling.

PubMed: 41298390
DOI: 10.1038/s41467-025-65578-2

Experimental method

ELECTRON MICROSCOPY (2.86 Å)