Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41467-020-20319-5
Title: Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8
Authors: Gong, Qin
Robinson, Kim
Xu, Chenrui
Huynh, Phuong Thao
Chong, Kelvin Han Chung
Tan, Eddie Yong Jun
Zhang, Jiawen
Boo, Zhao Zhi
Teo, Daniel Eng Thiam
Lay, Kenneth
Zhang, Yaming
Lim, John Soon Yew
Goh, Wah Ing
Wright, Graham
Zhong, Franklin L.
Reversade, Bruno 
Wu, Bin
Issue Date: 8-Jan-2021
Publisher: Nature Research
Citation: Gong, Qin, Robinson, Kim, Xu, Chenrui, Huynh, Phuong Thao, Chong, Kelvin Han Chung, Tan, Eddie Yong Jun, Zhang, Jiawen, Boo, Zhao Zhi, Teo, Daniel Eng Thiam, Lay, Kenneth, Zhang, Yaming, Lim, John Soon Yew, Goh, Wah Ing, Wright, Graham, Zhong, Franklin L., Reversade, Bruno, Wu, Bin (2021-01-08). Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8. Nature Communications 12 (1) : 188. ScholarBank@NUS Repository. https://doi.org/10.1038/s41467-020-20319-5
Rights: Attribution 4.0 International
Abstract: Nod-like receptor (NLR) proteins activate pyroptotic cell death and IL-1 driven inflammation by assembling and activating the inflammasome complex. Closely related sensor proteins NLRP1 and CARD8 undergo unique auto-proteolysis-dependent activation and are implicated in auto-inflammatory diseases; however, their mechanisms of activation are not understood. Here we report the structural basis of how the activating domains (FIINDUPA-CARD) of NLRP1 and CARD8 self-oligomerize to assemble distinct inflammasome complexes. Recombinant FIINDUPA-CARD of NLRP1 forms a two-layered filament, with an inner core of oligomerized CARD surrounded by an outer ring of FIINDUPA. Biochemically, self-assembled NLRP1-CARD filaments are sufficient to drive ASC speck formation in cultured human cells—a process that is greatly enhanced by NLRP1-FIINDUPA which forms oligomers in vitro. The cryo-EM structures of NLRP1-CARD and CARD8-CARD filaments, solved here at 3.7 Å, uncover unique structural features that enable NLRP1 and CARD8 to discriminate between ASC and pro-caspase-1. In summary, our findings provide structural insight into the mechanisms of activation for human NLRP1 and CARD8 and reveal how highly specific signaling can be achieved by heterotypic CARD interactions within the inflammasome complexes. © 2021, The Author(s).
Source Title: Nature Communications
URI: https://scholarbank.nus.edu.sg/handle/10635/231978
ISSN: 2041-1723
DOI: 10.1038/s41467-020-20319-5
Rights: Attribution 4.0 International
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