<table><tr><td colspan='2'>[[6npy]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NPY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NPY FirstGlance]. <br>
<table><tr><td colspan='2'>[[6npy]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NPY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NPY FirstGlance]. <br>
6npy is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
[NLRP3_HUMAN] CINCA syndrome with NLRP3 mutations;Familial cold urticaria;Muckle-Wells syndrome. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.
Function
[NLRP3_HUMAN] As the sensor component of the NLRP3 inflammasome, plays a crucial role in innate immunity and inflammation. In response to pathogens and other damage-associated signals, initiates the formation of the inflammasome polymeric complex, made of NLRP3, PYCARD and CASP1 (and possibly CASP4 and CASP5). Recruitment of proCASP1 to the inflammasome promotes its activation and CASP1-catalyzed IL1B and IL18 maturation and secretion in the extracellular milieu. Activation of NLRP3 inflammasome is also required for HMGB1 secretion (PubMed:22801494). The active cytokines and HMGB1 stimulate inflammatory responses. Inflammasomes can also induce pyroptosis, an inflammatory form of programmed cell death. Under resting conditions, NLRP3 is autoinhibited. NLRP3 activation stimuli include extracellular ATP, reactive oxygen species, K(+) efflux, crystals of monosodium urate or cholesterol, beta-amyloid fibers, environmental or industrial particles and nanoparticles, etc. However, it is unclear what constitutes the direct NLRP3 activator. Independently of inflammasome activation, regulates the differentiation of T helper 2 (Th2) cells and has a role in Th2 cell-dependent asthma and tumor growth (By similarity). During Th2 differentiation, required for optimal IRF4 binding to IL4 promoter and for IRF4-dependent IL4 transcription. Binds to the consensus DNA sequence 5'-GRRGGNRGAG-3'. May also participate in the transcription of IL5, IL13, GATA3, CCR3, CCR4 and MAF (By similarity).[UniProtKB:Q8R4B8][1][2] [E2AK2_HUMAN] Following activation by double-stranded RNA in the presence of ATP, the kinase becomes autophosphorylated and can catalyze the phosphorylation of the translation initiation factor EIF2S1, which leads to an inhibition of the initiation of protein synthesis. Double-stranded RNA is generated during the course of a viral infection. In addition to serine/threonine-protein kinase activity, also has tyrosine-protein kinase activity: phosphorylates CDK1 upon DNA damage. CDK1 phosphorylation triggers CDK1 polyubiquitination and subsequent proteolysis, thus leading to G2 arrest.[3]
Publication Abstract from PubMed
The NLRP3 inflammasome can be activated by stimuli that include nigericin, uric acid crystals, amyloid-beta 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 A. 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.
Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome.,Sharif H, Wang L, Wang WL, Magupalli VG, Andreeva L, Qiao Q, Hauenstein AV, Wu Z, Nunez G, Mao Y, Wu H Nature. 2019 Jun;570(7761):338-343. doi: 10.1038/s41586-019-1295-z. Epub 2019 Jun, 12. PMID:31189953[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
↑ Lu B, Nakamura T, Inouye K, Li J, Tang Y, Lundback P, Valdes-Ferrer SI, Olofsson PS, Kalb T, Roth J, Zou Y, Erlandsson-Harris H, Yang H, Ting JP, Wang H, Andersson U, Antoine DJ, Chavan SS, Hotamisligil GS, Tracey KJ. Novel role of PKR in inflammasome activation and HMGB1 release. Nature. 2012 Aug 30;488(7413):670-4. doi: 10.1038/nature11290. PMID:22801494 doi:http://dx.doi.org/10.1038/nature11290
↑ Haneklaus M, O'Neill LA, Coll RC. Modulatory mechanisms controlling the NLRP3 inflammasome in inflammation: recent developments. Curr Opin Immunol. 2013 Feb;25(1):40-5. doi: 10.1016/j.coi.2012.12.004. Epub 2013, Jan 7. PMID:23305783 doi:http://dx.doi.org/10.1016/j.coi.2012.12.004
↑ Yoon CH, Miah MA, Kim KP, Bae YS. New Cdc2 Tyr 4 phosphorylation by dsRNA-activated protein kinase triggers Cdc2 polyubiquitination and G2 arrest under genotoxic stresses. EMBO Rep. 2010 May;11(5):393-9. doi: 10.1038/embor.2010.45. Epub 2010 Apr 16. PMID:20395957 doi:http://dx.doi.org/10.1038/embor.2010.45
↑ Sharif H, Wang L, Wang WL, Magupalli VG, Andreeva L, Qiao Q, Hauenstein AV, Wu Z, Nunez G, Mao Y, Wu H. Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome. Nature. 2019 Jun;570(7761):338-343. doi: 10.1038/s41586-019-1295-z. Epub 2019 Jun, 12. PMID:31189953 doi:http://dx.doi.org/10.1038/s41586-019-1295-z
