TY - JOUR
T1 - Cryo-EM structure of the NLRC4CARD filament provides insights into how symmetric and asymmetric supramolecular structures drive inflammasome assembly
AU - Matyszewski, Mariusz
AU - Zheng, Weili
AU - Lueck, Jacob
AU - Antiochos, Brendan
AU - Egelman, Edward H.
AU - Sohn, Jungsan
N1 - Funding Information:
Acknowledgments—We thank the Sohn lab members for discussion and the staff at NCI NCEF for cryo-EM data collection. The Johns Hopkins Microscope Facility was supported by National Institutes of Health Grant S10 OD016734.
Funding Information:
This work was supported by Research Scholars Grant RG-15–224 from American Cancer Society (to J. S.), National Institutes of Health Grant R35GM0352569 (to E. H. E.), and Rheumatology Research Foundation and Cupid Foundation (to B.A.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the respon-sibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This article contains Fig. S1. The atomic coordinates and structure factors (code 6MKS) have been deposited in the Protein Data Bank (http://wwpdb.org/). The corresponding cryo-EM map was deposited in the Electron Microscopy Data Bank with accession code EMD-9137. 1 Both authors contributed equally to this work. 2To whom correspondence may be addressed. E-mail: egelman@virginia. edu. 3 To whom correspondence may be addressed. E-mail: jsohn@jhmi.edu.
Publisher Copyright:
© 2018 Matyszewski et al.
PY - 2018/12/28
Y1 - 2018/12/28
N2 - Inflammasomes are supramolecular signaling platforms integral to innate immune defense against invading pathogens. The NOD-like receptor (NLR) family apoptosis inhibitory protein (NAIP)䡠NLR family caspase-recruiting domain (CARD) domain-containing 4 (NLRC4) inflammasome recognizes intracellular bacteria and induces the polymerization of the caspase-1 protease, which in turn executes maturation of interleukin-1 (IL-1) and pyroptosis. Several high-resolution structures of the fully assembled NAIP䡠NLRC4 complex are available, but these structures do not resolve the architecture of the CARD filament in atomic detail. Here, we present the cryo-EM structure of the filament assembled by the CARD of human NLRC4 (NLRC4CARD) at 3.4 Å resolution. The structure revealed that the helical architecture of the NLRC4CARD filament is essentially identical to that of the downstream filament assembled by the CARD of caspase-1 (casp1CARD), but deviates from the split washer-like assembly of the NAIP䡠NLRC4 oligomer. Our results suggest that architectural complementarity is a major driver for the recognition between upstream and downstream CARD assemblies in inflammasomes. Furthermore, a Monte Carlo simulation of the NLRC4CARD filament assembly rationalized why an (un)decameric NLRC4 oligomer is optimal for assembling the helical base of the NLRC4CARD filament. Together, our results explain how symmetric and asymmetric supramolecular assemblies enable high-fidelity signaling in inflammasomes.
AB - Inflammasomes are supramolecular signaling platforms integral to innate immune defense against invading pathogens. The NOD-like receptor (NLR) family apoptosis inhibitory protein (NAIP)䡠NLR family caspase-recruiting domain (CARD) domain-containing 4 (NLRC4) inflammasome recognizes intracellular bacteria and induces the polymerization of the caspase-1 protease, which in turn executes maturation of interleukin-1 (IL-1) and pyroptosis. Several high-resolution structures of the fully assembled NAIP䡠NLRC4 complex are available, but these structures do not resolve the architecture of the CARD filament in atomic detail. Here, we present the cryo-EM structure of the filament assembled by the CARD of human NLRC4 (NLRC4CARD) at 3.4 Å resolution. The structure revealed that the helical architecture of the NLRC4CARD filament is essentially identical to that of the downstream filament assembled by the CARD of caspase-1 (casp1CARD), but deviates from the split washer-like assembly of the NAIP䡠NLRC4 oligomer. Our results suggest that architectural complementarity is a major driver for the recognition between upstream and downstream CARD assemblies in inflammasomes. Furthermore, a Monte Carlo simulation of the NLRC4CARD filament assembly rationalized why an (un)decameric NLRC4 oligomer is optimal for assembling the helical base of the NLRC4CARD filament. Together, our results explain how symmetric and asymmetric supramolecular assemblies enable high-fidelity signaling in inflammasomes.
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U2 - 10.1074/jbc.RA118.006050
DO - 10.1074/jbc.RA118.006050
M3 - Article
C2 - 30385506
AN - SCOPUS:85059241562
SN - 0021-9258
VL - 293
SP - 20240
EP - 20248
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 52
ER -