Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome

Article

关键词: CRYO-EM STRUCTURE;    CRYSTAL-STRUCTURE;    NEK7;    BINDING;    PHOSPHORYLATION;    RECOGNITION;    PREDICTION;    FEATURES;    REVEALS;    SYSTEM;   

DOI  :  10.1038/s41586-019-1295-z

来源: SCIE

【 摘 要 】

The NLRP3 inflammasome can be activated by stimuli that include nigericin, uric acid crystals, amyloid-beta fibrils and extracellnlar ATP. The mitotic kinase NEK7 licenses the assembly and activation of the NLRP3 inflammasome in interphase. Here we report a cryo-electron microscopy structure of inactive human NLRP3 in complex with NEK7, at a resolution of 3.8 angstrom. The earring-shaped NLRP3 consists of curved leucine -rich-repeat and globular NACHT domains, and the C-terminal lobe of NEK7 nestles against both NLRP3 domains. Structural recognition between NLRP3 and NEK7 is confirmed by mutagenesis both in vitro and in cells. Modelling of an active NLRP3-NEK7 conformation based on the NLRC4 inflammasome predicts an additional contact between an NLRP3-bound NEK7 and a neighbouring NLRP3. Mutations to this interface abolish the ability of NEK7 or NLRP3 to rescue NLRP3 activation in NEK7-knockout or NLRP3-knockout cells. These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome.

【 授权许可】

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