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| Title | Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome. |
|---|---|
| Journal, issue, pages | Nature, Vol. 570, Issue 7761, Page 338-343, Year 2019 |
| Publish date | Jun 12, 2019 |
 Authors | Humayun Sharif / Li Wang / Wei Li Wang / Venkat Giri Magupalli / Liudmila Andreeva / Qi Qiao / Arthur V Hauenstein / Zhaolong Wu / Gabriel Núñez / Youdong Mao / Hao Wu /   |
| PubMed Abstract | 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 ...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. |
 External links | Nature / PubMed:31189953 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.8 Å |
| Structure data | |
| Chemicals |  ChemComp-ADP: |
| Source |
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 Keywords |  IMMUNE SYSTEM / Inflammasome / Activator / Biological process Immunity / Inflammatory response / Innate immunity / Transcription / Transcription regulation Ligand / ATP binding / Nucleotide binding |
