Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome
Copyright policy )Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome
The NLRP3 inflammasome can be activated by stimuli that include nigericin, uric acid crystals, amyloid-β fibrils and extracellular 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 Å. 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.
- Boston Children's Hospital United States
- Harvard University United States
- Peking University China (People's Republic of)
- Peking University China (People's Republic of)
- University of Michigan–Flint United States
Models, Molecular, Inflammasomes, Cryoelectron Microscopy, Binding, Competitive, Protein Domains, Mutation, NLR Family, Pyrin Domain-Containing 3 Protein, Humans, NIMA-Related Kinases, Protein Multimerization, Protein Structure, Quaternary, Protein Binding
Models, Molecular, Inflammasomes, Cryoelectron Microscopy, Binding, Competitive, Protein Domains, Mutation, NLR Family, Pyrin Domain-Containing 3 Protein, Humans, NIMA-Related Kinases, Protein Multimerization, Protein Structure, Quaternary, Protein Binding
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).649 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 0.1% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 1% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 0.1%
Citations provided by BIP!Popularity provided by BIP!