National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R35GM122510
United States
Citation
Journal: Nat Commun / Year: 2021 Title: Distinct axial and lateral interactions within homologous filaments dictate the signaling specificity and order of the AIM2-ASC inflammasome. Authors: Mariusz Matyszewski / Weili Zheng / Jacob Lueck / Zachary Mazanek / Naveen Mohideen / Albert Y Lau / Edward H Egelman / Jungsan Sohn / Abstract: Inflammasomes are filamentous signaling platforms integral to innate immunity. Currently, little is known about how these structurally similar filaments recognize and distinguish one another. A cryo- ...Inflammasomes are filamentous signaling platforms integral to innate immunity. Currently, little is known about how these structurally similar filaments recognize and distinguish one another. A cryo-EM structure of the AIM2 filament reveals that the architecture of the upstream filament is essentially identical to that of the adaptor ASC filament. In silico simulations using Rosetta and molecular dynamics followed by biochemical and cellular experiments consistently demonstrate that individual filaments assemble bidirectionally. By contrast, the recognition between AIM2 and ASC requires at least one to be oligomeric and occurs in a head-to-tail manner. Using in silico mutagenesis as a guide, we also identify specific axial and lateral interfaces that dictate the recognition and distinction between AIM2 and ASC filaments. Together, the results here provide a robust framework for delineating the signaling specificity and order of inflammasomes.
A: Interferon-inducible protein AIM2 B: Interferon-inducible protein AIM2 C: Interferon-inducible protein AIM2 D: Interferon-inducible protein AIM2 E: Interferon-inducible protein AIM2 F: Interferon-inducible protein AIM2 G: Interferon-inducible protein AIM2 H: Interferon-inducible protein AIM2 I: Interferon-inducible protein AIM2 J: Interferon-inducible protein AIM2 K: Interferon-inducible protein AIM2 L: Interferon-inducible protein AIM2 M: Interferon-inducible protein AIM2 N: Interferon-inducible protein AIM2 O: Interferon-inducible protein AIM2 P: Interferon-inducible protein AIM2 Q: Interferon-inducible protein AIM2 R: Interferon-inducible protein AIM2 S: Interferon-inducible protein AIM2 T: Interferon-inducible protein AIM2 U: Interferon-inducible protein AIM2
Helical symmetry: (Circular symmetry: 3 / Dyad axis: no / N subunits divisor: 1 / Num. of operations: 7 / Rise per n subunits: 14 Å / Rotation per n subunits: 53.3 °)
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Components
#1: Protein
... Interferon-inducibleproteinAIM2 / Absent in melanoma 2
Mass: 13528.655 Da / Num. of mol.: 21 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: AIM2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: O14862
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Experimental details
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Experiment
Experiment
Method: ELECTRON MICROSCOPY
EM experiment
Aggregation state: FILAMENT / 3D reconstruction method: helical reconstruction
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