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Protein

NACHT, LRR and PYD domains-containing protein 3

Gene

NLRP3

Organism
Bos taurus (Bovine)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at transcript leveli

Functioni

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. 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 (By similarity). 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. 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).By similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi223 – 2308ATPPROSITE-ProRule annotation

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Activator

Keywords - Biological processi

Immunity, Inflammatory response, Innate immunity, Transcription, Transcription regulation

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiR-BTA-844456. The NLRP3 inflammasome.

Names & Taxonomyi

Protein namesi
Recommended name:
NACHT, LRR and PYD domains-containing protein 3
Gene namesi
Name:NLRP3
OrganismiBos taurus (Bovine)
Taxonomic identifieri9913 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaRuminantiaPecoraBovidaeBovinaeBos
Proteomesi
  • UP000009136 Componenti: Chromosome 7

Subcellular locationi

  • Cytoplasmcytosol By similarity
  • Inflammasome By similarity
  • Endoplasmic reticulum By similarity
  • Secreted By similarity
  • Nucleus By similarity

  • Note: In macrophages, under resting conditions, mainly located in the cytosol, on the endoplasmic reticulum. After stimulation with inducers of the NLRP3 inflammasome, mitochondria redistribute in the vicinity of the endoplasmic reticulum in the perinuclear region, which results in colocalization of NLRP3 on the endoplasmic reticulum and PYCARD on mitochondria, allowing the activation of inflammasome assembly. After the induction of pyroptosis, inflammasome specks are released into the extracellular space where they can further promote IL1B processing and where they can be engulfed by macrophages. Phagocytosis induces lysosomal damage and inflammasome activation in the recipient cells (By similarity). In the Th2 subset of CD4+ helper T-cells, mainly located in the nucleus. Nuclear localization depends upon KPNA2. In the Th1 subset of CD4+ helper T-cells, mainly cytoplasmic (By similarity).By similarity

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Endoplasmic reticulum, Inflammasome, Nucleus, Secreted

Pathology & Biotechi

Keywords - Diseasei

Amyloidosis

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 10311031NACHT, LRR and PYD domains-containing protein 3PRO_0000387568Add
BLAST

Post-translational modificationi

Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. Ubiquitination does not lead to degradation, but inhibits inflammasome activation (By similarity). Deubiquitination is catalyzed by BRCC3 and associated with NLRP3 activation and inflammasome assembly. This process can be induced by the activation of Toll-like receptors (by LPS), through a non-transcriptional pathway dependent on the mitochondrial production of reactive oxygen species, and by ATP (By similarity).By similarity

Keywords - PTMi

Ubl conjugation

Proteomic databases

PaxDbiA6QLE5.
PRIDEiA6QLE5.

Expressioni

Gene expression databases

BgeeiENSBTAG00000001273.

Interactioni

Subunit structurei

Sensor component of NLRP3 inflammasomes. Inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens and other damage-associated signals and play critical roles in innate immunity and inflammation. The core of NLRP3 inflammasomes consists of a signal sensor component (NLRP3), an adapter (ASC/PYCARD), which recruits an effector proinflammatory caspase (CASP1 and, possibly, CASP4 and CASP5). Within the complex, NLRP3 and PYCARD interact via their respective pyrin domains. This interaction initiates speck formation (nucleation) which greatly enhances further addition of soluble PYCARD molecules to the speck in a prion-like polymerization process. NLRP3 localizes at the end of each PYCARD filament. Clustered PYCARD nucleates the formation of CASP1 filaments through the interaction of their respective CARD domains, acting as a platform for CASP1 polymerization. CASP1 filament formation increases local enzyme concentration, resulting in trans-autocleavage and activation. Active CASP1 then processes IL1B and IL18 precursors, leading to the release of mature cytokines in the extracellular milieu and inflammatory response. Reconstituted ternary inflammasomes show star-shaped structures, in which multiple filaments, containing CASP1, protrude radially from a single central hub, containing the sensor protein and PYCARD. In this complex, the sensor protein is sub-stoichiometric to PYCARD, and PYCARD is further substoichiometric to CASP1, suggesting amplifications of signal transduction from the sensor, via the adapter, to the effector. Interacts with MEFV; this interaction targets NLRP3 to degradation by autophagy, hence preventing excessive IL1B- and IL18-mediated inflammation. Interacts with GBP5 (via pyrin domain); this interaction promotes inflammasome assembly in response to microbial and soluble, but not crystalline, agents. Interacts with EIF2AK2/PKR; this interaction requires EIF2AK2 activity, is accompanied by EIF2AK2 autophosphorylation and promotes inflammasome assembly in response to specific stimuli. Interacts with PML (isoform PML-1) (via the leucine-rich repeat (LRR) domain); PML-mediated increase in NLRP3 inflammasome activation does not depend upon this interaction (By similarity). Directly interacts with IRF4 (via the LRR domain); this interaction is required for optimal IRF4 binding to IL4 promoter and efficient IL4 transactivation during differentiation of Th2 helper T-cells (By similarity).By similarity

GO - Molecular functioni

Protein-protein interaction databases

STRINGi9913.ENSBTAP00000001675.

Structurei

3D structure databases

ProteinModelPortaliA6QLE5.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini1 – 9393PyrinPROSITE-ProRule annotationAdd
BLAST
Domaini217 – 533317NACHTPROSITE-ProRule annotationAdd
BLAST
Repeati737 – 75721LRR 1Add
BLAST
Repeati766 – 78722LRR 2Add
BLAST
Repeati794 – 81421LRR 3Add
BLAST
Repeati823 – 84422LRR 4Add
BLAST
Repeati851 – 87121LRR 5Add
BLAST
Repeati880 – 90122LRR 6Add
BLAST
Repeati908 – 92922LRR 7Add
BLAST
Repeati937 – 95822LRR 8Add
BLAST
Repeati965 – 98622LRR 9Add
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi688 – 6947Poly-Glu

Domaini

The pyrin domain (also called DAPIN domain or PYD) is involved in PYCARD-binding.By similarity
The LRR domain mediates the interaction with IRF4 and PML.By similarity
Intramolecular interactions between NACHT and leucine-rich repeat (LRR) domains may be important for autoinhibition in the absence of activating signal.By similarity

Sequence similaritiesi

Belongs to the NLRP family.Curated
Contains 9 LRR (leucine-rich) repeats.Curated
Contains 1 NACHT domain.PROSITE-ProRule annotation
Contains 1 pyrin domain.PROSITE-ProRule annotation

Keywords - Domaini

Leucine-rich repeat, Repeat

Phylogenomic databases

eggNOGiENOG410IE5X. Eukaryota.
ENOG4111H3D. LUCA.
GeneTreeiENSGT00840000129675.
HOGENOMiHOG000294064.
InParanoidiA6QLE5.
KOiK12800.
OMAiAMAKWIF.
OrthoDBiEOG091G01CG.

Family and domain databases

Gene3Di1.10.533.10. 1 hit.
3.80.10.10. 1 hit.
InterProiIPR004020. DAPIN.
IPR011029. DEATH-like_dom.
IPR032675. L_dom-like.
IPR001611. Leu-rich_rpt.
IPR029495. NACHT-assoc.
IPR007111. NACHT_NTPase.
IPR027417. P-loop_NTPase.
[Graphical view]
PfamiPF14484. FISNA. 1 hit.
PF13516. LRR_6. 5 hits.
PF02758. PYRIN. 1 hit.
[Graphical view]
SMARTiSM01288. FISNA. 1 hit.
SM01289. PYRIN. 1 hit.
[Graphical view]
SUPFAMiSSF47986. SSF47986. 1 hit.
SSF52540. SSF52540. 2 hits.
PROSITEiPS50824. DAPIN. 1 hit.
PS50837. NACHT. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

A6QLE5-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MRMVSVRCKL ARYLEDLEDI DFKKFKMHLE DYPSQKGCTS IPRGQTEKAD
60 70 80 90 100
HVDLATLMID FNGEEKAWAM AKWIFAAINR RDLYEKAKRE EPEWENANIS
110 120 130 140 150
VLSQEESLEE EWMGLLGYLS RISICRKKKD YCKKYRKYVR SKFQCIKDRN
160 170 180 190 200
ARLGESVNLN KRFTRLRLIK EHRSQQEREH ELLAIGRTWA KIQDSPVSSV
210 220 230 240 250
NLELLFDPED QHSEPVHTVV FQGAAGIGKT ILARKIMLDW ASEKLYQDRF
260 270 280 290 300
DYLFYIHCRE VSLGTQRSLG DLIASCCPGP NPPIGKIVSK PSRILFLMDG
310 320 330 340 350
FDELQGAFDE HTEALCTNWR KVERGDILLS SLIRKRLLPE ASLLITTRPV
360 370 380 390 400
ALEKLQHLLG QARHVEILGF SEARRKEYFL KYFSDEQQAR EAFRLIQENE
410 420 430 440 450
ILFTMCFIPL VCWIVCTGLK QQMDSGKSLA RTSKTTTAVY IFFLSSLLQS
460 470 480 490 500
QGGSQENHNS ATLWGLCSLA ADGIWNQKIL FQECDLRNHG LQKADVSAFL
510 520 530 540 550
RMNLFQKEVD CEKFYSFIHM TFQEFFAAMY YLLEEDNHGE MRNTPQACSK
560 570 580 590 600
LPNRDVKVLL ENYGKFEKGY LIFVVRFLFG LINQERTSYL EKKLSCKISQ
610 620 630 640 650
KIRLELLKWI EAKANAKTLQ IEPSQLELFY CLYEMQEEDF VQRAMSHFPK
660 670 680 690 700
IEIKLSTRMD HVVSSFCIEN CRHVESLSLR LLHNSPKEEE EEEEVRHSHM
710 720 730 740 750
DRSVLSDFEV AYSQGLVNYL TSSICRGIFS VLSNNWNLTE LNLSGNTLGD
760 770 780 790 800
PGMNVLCETL QQPGCNIRRL WLGQCCLSHQ CCFNISSVLS NNQKLVELDL
810 820 830 840 850
SHNALGDFGI RLLCVGLRHL FCNLKKLWLV SCCLTSASCE DLASVLSTNH
860 870 880 890 900
SLTRLYLGEN ALGDSGVGIL CEKVKNPHCN LQKLGLVNSG LTSGCCPALS
910 920 930 940 950
SVLSTNQNLT HLYLQGNALG DMGVKLLCEG LLHRNCKLQV LELDNCSLTS
960 970 980 990 1000
HCCWDLSTLL TSNQSLRKLC LGNNDLGDLG VMLLCEVLKQ QGCLLKSLRL
1010 1020 1030
CEMYFNYDTK RALETLQEEK PELTIVFEPS R
Length:1,031
Mass (Da):118,137
Last modified:August 21, 2007 - v1
Checksum:i570A960997634381
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BC147936 mRNA. Translation: AAI47937.1.
RefSeqiNP_001095689.1. NM_001102219.1.
XP_010805479.1. XM_010807177.2.
UniGeneiBt.61644.

Genome annotation databases

EnsembliENSBTAT00000001675; ENSBTAP00000001675; ENSBTAG00000001273.
GeneIDi538639.
KEGGibta:538639.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BC147936 mRNA. Translation: AAI47937.1.
RefSeqiNP_001095689.1. NM_001102219.1.
XP_010805479.1. XM_010807177.2.
UniGeneiBt.61644.

3D structure databases

ProteinModelPortaliA6QLE5.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi9913.ENSBTAP00000001675.

Proteomic databases

PaxDbiA6QLE5.
PRIDEiA6QLE5.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSBTAT00000001675; ENSBTAP00000001675; ENSBTAG00000001273.
GeneIDi538639.
KEGGibta:538639.

Organism-specific databases

CTDi114548.

Phylogenomic databases

eggNOGiENOG410IE5X. Eukaryota.
ENOG4111H3D. LUCA.
GeneTreeiENSGT00840000129675.
HOGENOMiHOG000294064.
InParanoidiA6QLE5.
KOiK12800.
OMAiAMAKWIF.
OrthoDBiEOG091G01CG.

Enzyme and pathway databases

ReactomeiR-BTA-844456. The NLRP3 inflammasome.

Gene expression databases

BgeeiENSBTAG00000001273.

Family and domain databases

Gene3Di1.10.533.10. 1 hit.
3.80.10.10. 1 hit.
InterProiIPR004020. DAPIN.
IPR011029. DEATH-like_dom.
IPR032675. L_dom-like.
IPR001611. Leu-rich_rpt.
IPR029495. NACHT-assoc.
IPR007111. NACHT_NTPase.
IPR027417. P-loop_NTPase.
[Graphical view]
PfamiPF14484. FISNA. 1 hit.
PF13516. LRR_6. 5 hits.
PF02758. PYRIN. 1 hit.
[Graphical view]
SMARTiSM01288. FISNA. 1 hit.
SM01289. PYRIN. 1 hit.
[Graphical view]
SUPFAMiSSF47986. SSF47986. 1 hit.
SSF52540. SSF52540. 2 hits.
PROSITEiPS50824. DAPIN. 1 hit.
PS50837. NACHT. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiNLRP3_BOVIN
AccessioniPrimary (citable) accession number: A6QLE5
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 3, 2009
Last sequence update: August 21, 2007
Last modified: September 7, 2016
This is version 81 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.