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Protein

NLR family CARD domain-containing protein 4

Gene

Nlrc4

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Key component of inflammasomes that indirectly senses specific proteins from pathogenic bacteria and fungi and responds by assembling an inflammasome complex that promotes caspase-1 activation, cytokine production and macrophage pyroptosis. The NLRC4 inflammasome is activated as part of the innate immune response to a range of intracellular bacteria. It senses pathogenic proteins of the type III secretion system (T3SS) and type IV secretion system (T4SS) such as flagellin and PrgJ-like rod proteins via the Naip proteins (Naip1, Naip2 or Naip5): specific Naip proteins recognize and bind pathogenic proteins, driving assembly and activation of the NLRC4 inflammasome. The NLRC4 inflammasome senses Gram-negative bacteria such as L.pneumophila and P.aeruginosa, enteric pathogens S.typhimurium (Salmonella) and S.flexneri and fungal pathogen C.albicans. In intestine, the NLRC4 inflammasome is able to discriminate between commensal and pathogenic bacteria and specifically drives production of interleukin-1 beta (IL1B) in response to infection by Salmonella or P.aeruginosa. In case of L.pneumophila infection the inflammasome acts by activating caspase-7.16 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei135ATPCombined sources1 Publication1
Binding sitei443ATPCombined sources1 Publication1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi172 – 177ATPCombined sources1 Publication6

GO - Molecular functioni

GO - Biological processi

Keywordsi

Biological processApoptosis, Immunity, Inflammatory response, Innate immunity
LigandATP-binding, Nucleotide-binding

Names & Taxonomyi

Protein namesi
Recommended name:
NLR family CARD domain-containing protein 4
Alternative name(s):
Caspase recruitment domain-containing protein 12
Ice protease-activating factor
Short name:
Ipaf
Gene namesi
Name:Nlrc4
Synonyms:Card12, Ipaf
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 17

Organism-specific databases

MGIiMGI:3036243 Nlrc4

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Disruption phenotypei

Mice show defects in inflammasome function in response to S.typhimurium (Salmonella) infection. Differences are however observed depending on the strain background: in a C57BL/6J strain background, no striking differences are observed compared to wild-type mice following Salmonella infection. While in a BALB/c strain background, mice are highly susceptible to orogastric but not intraperitoneal infection with Salmonella: enhanced lethality is preceded by impaired expression of endothelial adhesion molecules, lower neutrophil recruitment and poor intestinal pathogen clearance.3 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi443H → L: Constitutively active. 1 Publication1
Mutagenesisi533S → A: Abolishes phosphorylation and prevents activation of caspase-1 and pyroptosis in response to S.typhimurium. 1 Publication1
Mutagenesisi533S → D: Mimics phosphorylation; causes rapid macrophage pyroptosis without infection. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00004199751 – 1024NLR family CARD domain-containing protein 4Add BLAST1024

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei533Phosphoserine2 Publications1

Post-translational modificationi

Phosphorylated at Ser-533 following infection of macrophages with S.typhimurium (Salmonella). Phosphorylation is essential for NLRC4 inflammasome function to promote caspase-1 activation and pyroptosis. PRKCD phosphorylates Ser-533 in vitro.2 Publications

Keywords - PTMi

Phosphoprotein

Proteomic databases

MaxQBiQ3UP24
PaxDbiQ3UP24
PeptideAtlasiQ3UP24
PRIDEiQ3UP24

PTM databases

iPTMnetiQ3UP24
PhosphoSitePlusiQ3UP24

Expressioni

Tissue specificityi

Expressed by intestinal mononuclear phagocytes.1 Publication

Gene expression databases

BgeeiENSMUSG00000039193 Expressed in 15 organ(s), highest expression level in colon

Interactioni

Subunit structurei

Homooligomer; homooligomerizes following activation of Naip proteins by pathogenic proteins such as S.typhimurium (Salmonella) flagellin or PrgJ (PubMed:23765277, PubMed:26449474, PubMed:26585513, PubMed:29146805). Component of the NLRC4 inflammasome, at least composed of NLRC4, caspase-1 (CASP1) and some NAIP protein (Naip, Naip2 or Naip5) (PubMed:21874021, PubMed:21918512, PubMed:26585513). Interacts with Naip5 and Naip6; following Naip5 and Naip6 engagement by Salmonella flagellin (PubMed:21874021, PubMed:21918512, PubMed:29182158, PubMed:29146805). Interacts with Naip2; following Naip2 engagement by Salmonella PrgJ (PubMed:21874021, PubMed:21918512, PubMed:26449474). The inflammasome is a huge complex that contains multiple copies of NLRC4 and a single Naip protein chain (PubMed:26449474, PubMed:29146805). Interacts with EIF2AK2/PKR (By similarity).By similarity6 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

IntActiQ3UP24, 6 interactors
STRINGi10090.ENSMUSP00000059637

Structurei

Secondary structure

11024
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ3UP24
SMRiQ3UP24
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini1 – 88CARDPROSITE-ProRule annotationAdd BLAST88
Domaini163 – 476NACHTPROSITE-ProRule annotationAdd BLAST314
Repeati578 – 598LRR 11 PublicationAdd BLAST21
Repeati656 – 679LRR 21 PublicationAdd BLAST24
Repeati735 – 758LRR 31 PublicationAdd BLAST24
Repeati762 – 785LRR 41 PublicationAdd BLAST24
Repeati787 – 812LRR 51 PublicationAdd BLAST26
Repeati824 – 847LRR 61 PublicationAdd BLAST24
Repeati848 – 870LRR 71 PublicationAdd BLAST23
Repeati878 – 902LRR 81 PublicationAdd BLAST25
Repeati911 – 933LRR 91 PublicationAdd BLAST23
Repeati936 – 963LRR 101 PublicationAdd BLAST28
Repeati965 – 985LRR 111 PublicationAdd BLAST21
Repeati999 – 1021LRR 121 PublicationAdd BLAST23

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni95 – 298Nucleotide-binding domain (NBD)Add BLAST204
Regioni356 – 463Winged-helix domain (WHD)Add BLAST108

Domaini

In an autoinhibited form the C-terminal leucine-rich repeat (LRR) domain is positioned to sterically occlude one side of the NBD domain and consequently sequester NLRC4 in a monomeric state. An ADP-mediated interaction between the NBD and the WHD also contributes to the autoinhibition (PubMed:23765277).1 Publication

Keywords - Domaini

Leucine-rich repeat, Repeat

Phylogenomic databases

eggNOGiENOG410IHIG Eukaryota
ENOG410YI2E LUCA
GeneTreeiENSGT00500000044782
HOGENOMiHOG000059630
HOVERGENiHBG050790
InParanoidiQ3UP24
KOiK12805
OMAiYERATES
OrthoDBiEOG091G0A33
PhylomeDBiQ3UP24
TreeFamiTF336864

Family and domain databases

Gene3Di3.80.10.10, 2 hits
InterProiView protein in InterPro
IPR001315 CARD
IPR011029 DEATH-like_dom_sf
IPR032675 LRR_dom_sf
IPR007111 NACHT_NTPase
IPR027417 P-loop_NTPase
PfamiView protein in Pfam
PF00619 CARD, 1 hit
PF05729 NACHT, 1 hit
SUPFAMiSSF47986 SSF47986, 1 hit
SSF52540 SSF52540, 1 hit
PROSITEiView protein in PROSITE
PS50209 CARD, 1 hit
PS50837 NACHT, 1 hit

Sequencei

Sequence statusi: Complete.

Q3UP24-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MNFIRNNRRA LIQRMGLTVT KQICDDLFAL NVLNNQEANV IYCEPLEQEA
60 70 80 90 100
ARKIIHMTMQ KGSAACNLFL KSLENWDYFV YQDLTGQNLS YQVTEEDLNV
110 120 130 140 150
LAQNLKDLYN SPAFLNFYPL GEDIDIIFNL EKTFTEPIMW KKDHRHHRVE
160 170 180 190 200
QLTLGSLLEA LKSPCLIEGE SGKGKSTLLQ RIAMLWASGG CRALKGFRLV
210 220 230 240 250
FFIHLRSARG GLFETLYDQL LNIPDFISKP TFKALLLKLH KEVLFLLDGY
260 270 280 290 300
NEFHPQNCPE IEALIKENHR FKNMVIVTTT TECLRHIRHV GALTAEVGDM
310 320 330 340 350
TEDSAKDLIE AVLVPDQVER LWAQIQESRC LRNLMKTPLF VVITCAIQMG
360 370 380 390 400
RQEFQAHTQT MLFQTFYDLL IQKNSHRYRG GASGDFARSL DYCGDLALEG
410 420 430 440 450
VFAHKFDFEP EHGSSMNEDV LVTIGLLCKY TAQRLKPTYK FFHKSFQEYT
460 470 480 490 500
AGRRLSSLLT SKEPEEVSKG NSYLNKMVSI SDITSLYGNL LLYTCGSSTE
510 520 530 540 550
ATRAVMRHLA MVYQHGSLQG LSVTKRPLWR QESIQSLRNT TEQDVLKAIN
560 570 580 590 600
VNSFVECGIN LFSESMSKSD LSQEFEAFFQ GKSLYINSEN IPDYLFDFFE
610 620 630 640 650
YLPNCASALD FVKLDFYERA TESQDKAEEN VPGVHTEGPS ETYIPPRAVS
660 670 680 690 700
LFFNWKQEFK TLEVTLRDIN KLNKQDIKYL GKIFSSATNL RLHIKRCAAM
710 720 730 740 750
AGRLSSVLRT CKNMHTLMVE ASPLTTDDEQ YITSVTGLQN LSIHRLHTQQ
760 770 780 790 800
LPGGLIDSLG NLKNLERLIL DDIRMNEEDA KNLAEGLRSL KKMRLLHLTH
810 820 830 840 850
LSDIGEGMDY IVKSLSEESC DLQEMKLVAC CLTANSVKVL AQNLHNLIKL
860 870 880 890 900
SILDISENYL EKDGNEALQE LIGRLGVLGE LTTLMLPWCW DVHTSLPKLL
910 920 930 940 950
KQLEGTPGLA KLGLKNWRLR DEEIKSLGEF LEMNPLRDLQ QLDLAGHCVS
960 970 980 990 1000
SDGWLYFMNV FENLKQLVFF DFSTEEFLPD AALVRKLSQV LSKLTLLQEV
1010 1020
KLTGWEFDDY DISAIKGTFK LVTA
Length:1,024
Mass (Da):116,749
Last modified:October 11, 2005 - v1
Checksum:i15F192E8F00FF017
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti99N → S in BAE42570 (PubMed:16141072).Curated1
Sequence conflicti385D → N in BAE42570 (PubMed:16141072).Curated1
Sequence conflicti515H → Y in BAE42570 (PubMed:16141072).Curated1
Sequence conflicti670N → S in BAE42570 (PubMed:16141072).Curated1
Sequence conflicti756I → V in BAE42570 (PubMed:16141072).Curated1
Sequence conflicti782N → S in BAE42570 (PubMed:16141072).Curated1
Sequence conflicti799T → I in BAE42570 (PubMed:16141072).Curated1
Sequence conflicti948C → R in BAE42570 (PubMed:16141072).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK143864 mRNA Translation: BAE25573.1
AK171624 mRNA Translation: BAE42570.1
CT033749 Genomic DNA No translation available.
CCDSiCCDS37692.1
RefSeqiNP_001028539.1, NM_001033367.3
XP_006524409.1, XM_006524346.3
XP_017172979.1, XM_017317490.1
XP_017172980.1, XM_017317491.1
UniGeneiMm.311884

Genome annotation databases

EnsembliENSMUST00000052124; ENSMUSP00000059637; ENSMUSG00000039193
GeneIDi268973
KEGGimmu:268973
UCSCiuc008doc.1 mouse

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK143864 mRNA Translation: BAE25573.1
AK171624 mRNA Translation: BAE42570.1
CT033749 Genomic DNA No translation available.
CCDSiCCDS37692.1
RefSeqiNP_001028539.1, NM_001033367.3
XP_006524409.1, XM_006524346.3
XP_017172979.1, XM_017317490.1
XP_017172980.1, XM_017317491.1
UniGeneiMm.311884

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3JBLelectron microscopy4.50A/B/C/D/E/F/G/H/I/J/K93-1024[»]
4KXFX-ray3.20B/D/F/H/K/L/N/P1-1024[»]
5AJ2electron microscopy40.00A1-355[»]
B356-580[»]
C580-1024[»]
6B5Belectron microscopy5.20B/C1-1024[»]
ProteinModelPortaliQ3UP24
SMRiQ3UP24
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiQ3UP24, 6 interactors
STRINGi10090.ENSMUSP00000059637

PTM databases

iPTMnetiQ3UP24
PhosphoSitePlusiQ3UP24

Proteomic databases

MaxQBiQ3UP24
PaxDbiQ3UP24
PeptideAtlasiQ3UP24
PRIDEiQ3UP24

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000052124; ENSMUSP00000059637; ENSMUSG00000039193
GeneIDi268973
KEGGimmu:268973
UCSCiuc008doc.1 mouse

Organism-specific databases

CTDi58484
MGIiMGI:3036243 Nlrc4

Phylogenomic databases

eggNOGiENOG410IHIG Eukaryota
ENOG410YI2E LUCA
GeneTreeiENSGT00500000044782
HOGENOMiHOG000059630
HOVERGENiHBG050790
InParanoidiQ3UP24
KOiK12805
OMAiYERATES
OrthoDBiEOG091G0A33
PhylomeDBiQ3UP24
TreeFamiTF336864

Miscellaneous databases

PROiPR:Q3UP24
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000039193 Expressed in 15 organ(s), highest expression level in colon

Family and domain databases

Gene3Di3.80.10.10, 2 hits
InterProiView protein in InterPro
IPR001315 CARD
IPR011029 DEATH-like_dom_sf
IPR032675 LRR_dom_sf
IPR007111 NACHT_NTPase
IPR027417 P-loop_NTPase
PfamiView protein in Pfam
PF00619 CARD, 1 hit
PF05729 NACHT, 1 hit
SUPFAMiSSF47986 SSF47986, 1 hit
SSF52540 SSF52540, 1 hit
PROSITEiView protein in PROSITE
PS50209 CARD, 1 hit
PS50837 NACHT, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiNLRC4_MOUSE
AccessioniPrimary (citable) accession number: Q3UP24
Secondary accession number(s): Q3TAU8
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 31, 2012
Last sequence update: October 11, 2005
Last modified: November 7, 2018
This is version 109 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
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Main funding by: National Institutes of Health

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