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Protein

NLR family CARD domain-containing protein 4

Gene

Nlrc4

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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-7.14 Publications

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi169 – 176ATP8

GO - Molecular functioni

GO - Biological processi

  • activation of cysteine-type endopeptidase activity involved in apoptotic process Source: HGNC
  • activation of innate immune response Source: UniProtKB
  • apoptotic process Source: UniProtKB-KW
  • defense response to bacterium Source: UniProtKB
  • detection of bacterium Source: UniProtKB
  • inflammatory response Source: UniProtKB
  • inhibition of cysteine-type endopeptidase activity involved in apoptotic process Source: GO_Central
  • innate immune response Source: UniProtKB-KW
  • interleukin-1 beta secretion Source: UniProtKB
  • mitotic spindle assembly Source: GO_Central
  • positive regulation of apoptotic process Source: MGI
  • positive regulation of NF-kappaB transcription factor activity Source: MGI
  • protein homooligomerization Source: UniProtKB
  • pyroptosis Source: UniProtKB
  • regulation of apoptotic process Source: MGI
  • regulation of cysteine-type endopeptidase activity involved in apoptotic process Source: MGI
  • regulation of signal transduction Source: GO_Central
Complete GO annotation...

Keywords - Biological processi

Apoptosis, Immunity, Inflammatory response, Innate immunity

Keywords - Ligandi

ATP-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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 17

Organism-specific databases

MGIiMGI:3036243. Nlrc4.

Subcellular locationi

GO - Cellular componenti

  • cytosol Source: UniProtKB
  • IPAF inflammasome complex Source: UniProtKB
  • nucleus Source: GO_Central
  • spindle microtubule Source: GO_Central
Complete GO annotation...

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.

Interactioni

Subunit structurei

Homooligomer; homooligomerizes following activation of Naip proteins by pathogenic proteins such as S.typhimurium (Salmonella) flagellin or PrgJ. Component of the NLRC4 inflammasome, at least composed of NLRC4, caspase-1 (CASP1) and some NAIP protein (Naip, Naip2 or Naip5). Interacts with Naip5 and Naip6; following Naip5 and Naip6 engagement by Salmonella flagellin. Interacts with Naip2; following Naip2 engagement by Salmonella PrgJ. Interacts with EIF2AK2/PKR (By similarity).By similarity

GO - Molecular functioni

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000059637.

Structurei

Secondary structure

11024
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi95 – 109Combined sources15
Helixi112 – 115Combined sources4
Turni130 – 133Combined sources4
Beta strandi139 – 142Combined sources4
Beta strandi148 – 152Combined sources5
Helixi154 – 159Combined sources6
Beta strandi163 – 168Combined sources6
Helixi175 – 188Combined sources14
Helixi193 – 196Combined sources4
Beta strandi198 – 204Combined sources7
Helixi205 – 207Combined sources3
Helixi212 – 220Combined sources9
Helixi229 – 239Combined sources11
Helixi240 – 242Combined sources3
Beta strandi243 – 248Combined sources6
Helixi250 – 252Combined sources3
Turni255 – 257Combined sources3
Helixi259 – 266Combined sources8
Turni269 – 271Combined sources3
Beta strandi274 – 278Combined sources5
Helixi284 – 287Combined sources4
Turni288 – 290Combined sources3
Beta strandi292 – 297Combined sources6
Helixi302 – 312Combined sources11
Helixi315 – 327Combined sources13
Helixi329 – 334Combined sources6
Helixi338 – 350Combined sources13
Helixi359 – 374Combined sources16
Helixi375 – 377Combined sources3
Helixi386 – 403Combined sources18
Helixi416 – 424Combined sources9
Beta strandi426 – 429Combined sources4
Helixi444 – 459Combined sources16
Helixi464 – 475Combined sources12
Helixi480 – 485Combined sources6
Helixi488 – 497Combined sources10
Helixi499 – 509Combined sources11
Helixi519 – 521Combined sources3
Helixi534 – 538Combined sources5
Helixi542 – 565Combined sources24
Helixi572 – 579Combined sources8
Beta strandi583 – 589Combined sources7
Helixi593 – 601Combined sources9
Helixi603 – 608Combined sources6
Beta strandi609 – 618Combined sources10
Helixi646 – 654Combined sources9
Beta strandi659 – 668Combined sources10
Helixi674 – 684Combined sources11
Beta strandi687 – 696Combined sources10
Helixi703 – 707Combined sources5
Beta strandi712 – 721Combined sources10
Helixi726 – 734Combined sources9
Beta strandi740 – 746Combined sources7
Turni755 – 758Combined sources4
Beta strandi767 – 773Combined sources7
Helixi777 – 787Combined sources11
Beta strandi794 – 800Combined sources7
Helixi807 – 816Combined sources10
Beta strandi824 – 830Combined sources7
Helixi834 – 843Combined sources10
Helixi844 – 846Combined sources3
Beta strandi852 – 854Combined sources3
Helixi864 – 873Combined sources10
Helixi874 – 877Combined sources4
Beta strandi883 – 886Combined sources4
Helixi892 – 895Combined sources4
Helixi896 – 902Combined sources7
Helixi903 – 905Combined sources3
Beta strandi911 – 916Combined sources6
Helixi921 – 933Combined sources13
Beta strandi941 – 946Combined sources6
Helixi951 – 961Combined sources11
Beta strandi969 – 971Combined sources3
Beta strandi975 – 977Combined sources3
Helixi981 – 993Combined sources13
Beta strandi999 – 1001Combined sources3
Beta strandi1008 – 1010Combined sources3
Helixi1012 – 1015Combined sources4
Beta strandi1018 – 1022Combined sources5

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[»]
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

Sequence similaritiesi

Contains 1 CARD domain.PROSITE-ProRule annotation
Contains 12 LRR (leucine-rich) repeats.Curated
Contains 1 NACHT domain.PROSITE-ProRule annotation

Keywords - Domaini

Leucine-rich repeat, Repeat

Phylogenomic databases

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

Family and domain databases

Gene3Di1.10.533.10. 1 hit.
3.80.10.10. 1 hit.
InterProiIPR001315. CARD.
IPR011029. DEATH-like_dom.
IPR032675. L_dom-like.
IPR007111. NACHT_NTPase.
IPR027417. P-loop_NTPase.
[Graphical view]
PfamiPF00619. CARD. 1 hit.
[Graphical view]
SUPFAMiSSF47986. SSF47986. 1 hit.
SSF52540. SSF52540. 1 hit.
PROSITEiPS50209. CARD. 1 hit.
PS50837. NACHT. 1 hit.
[Graphical view]

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.

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[»]
ProteinModelPortaliQ3UP24.
SMRiQ3UP24.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

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.
OMAiDLFVWNV.
OrthoDBiEOG091G0A33.
PhylomeDBiQ3UP24.
TreeFamiTF336864.

Miscellaneous databases

PROiQ3UP24.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000039193.

Family and domain databases

Gene3Di1.10.533.10. 1 hit.
3.80.10.10. 1 hit.
InterProiIPR001315. CARD.
IPR011029. DEATH-like_dom.
IPR032675. L_dom-like.
IPR007111. NACHT_NTPase.
IPR027417. P-loop_NTPase.
[Graphical view]
PfamiPF00619. CARD. 1 hit.
[Graphical view]
SUPFAMiSSF47986. SSF47986. 1 hit.
SSF52540. SSF52540. 1 hit.
PROSITEiPS50209. CARD. 1 hit.
PS50837. NACHT. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiNLRC4_MOUSE
AccessioniPrimary (citable) accession number: Q3UP24
Secondary accession number(s): Q3TAU8
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 31, 2012
Last sequence update: October 11, 2005
Last modified: November 30, 2016
This is version 97 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

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
  3. 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.