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TitleStructural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8.
Journal, issue, pagesNat Commun, Vol. 12, Issue 1, Page 188, Year 2021
Publish dateJan 8, 2021
AuthorsQin Gong / Kim Robinson / Chenrui Xu / Phuong Thao Huynh / Kelvin Han Chung Chong / Eddie Yong Jun Tan / Jiawen Zhang / Zhao Zhi Boo / Daniel Eng Thiam Teo / Kenneth Lay / Yaming Zhang / John Soon Yew Lim / Wah Ing Goh / Graham Wright / Franklin L Zhong / Bruno Reversade / Bin Wu /
PubMed AbstractNod-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 ...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 (FIIND-CARD) of NLRP1 and CARD8 self-oligomerize to assemble distinct inflammasome complexes. Recombinant FIIND-CARD of NLRP1 forms a two-layered filament, with an inner core of oligomerized CARD surrounded by an outer ring of FIIND. 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-FIIND 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.
External linksNat Commun / PubMed:33420028 / PubMed Central
MethodsEM (helical sym.)
Resolution3.3 - 4.1 Å
Structure data

EMDB-9943, PDB-6k7v:
Structure of NLRP1 CARD filament
Method: EM (helical sym.) / Resolution: 3.7 Å

EMDB-9946, PDB-6k8j:
Structure of NLRC4 CARD filament
Method: EM (helical sym.) / Resolution: 3.3 Å

EMDB-9947, PDB-6k99:
Structure of ASC CARD filament
Method: EM (helical sym.) / Resolution: 4.1 Å

EMDB-9948, PDB-6k9f:
Structure of unknow protein 4
Method: EM (helical sym.) / Resolution: 3.7 Å

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / filament

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