NALP4_HUMAN
ID NALP4_HUMAN Reviewed; 994 AA.
AC Q96MN2; Q86W87; Q96AY6;
DT 02-MAY-2002, integrated into UniProtKB/Swiss-Prot.
DT 12-JUN-2007, sequence version 3.
DT 03-AUG-2022, entry version 185.
DE RecName: Full=NACHT, LRR and PYD domains-containing protein 4 {ECO:0000305};
DE AltName: Full=Cancer/testis antigen 58;
DE Short=CT58;
DE AltName: Full=PAAD and NACHT-containing protein 2;
DE Short=PAN2;
DE AltName: Full=PYRIN and NACHT-containing protein 2;
DE AltName: Full=PYRIN-containing APAF1-like protein 4;
DE Short=PYPAF4;
DE AltName: Full=Ribonuclease inhibitor 2;
GN Name=NLRP4 {ECO:0000312|HGNC:HGNC:22943};
GN Synonyms=NALP4, PAN2, PYPAF4, RNH2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT THR-144.
RX PubMed=12563287; DOI=10.1038/nrm1019;
RA Tschopp J., Martinon F., Burns K.;
RT "NALPs: a novel protein family involved in inflammation.";
RL Nat. Rev. Mol. Cell Biol. 4:95-104(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, INTERACTION WITH
RP CHUK/IKKA, AND VARIANT THR-144.
RX PubMed=12093792; DOI=10.1074/jbc.m200446200;
RA Fiorentino L., Stehlik C., Oliveira V., Ariza M.E., Godzik A., Reed J.C.;
RT "A novel PAAD-containing protein that modulates NF-kappa B induction by
RT cytokines tumor necrosis factor-alpha and interleukin-1beta.";
RL J. Biol. Chem. 277:35333-35340(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), LACK OF INTERACTION WITH ASC, AND
RP VARIANT THR-144.
RX PubMed=12387869; DOI=10.1016/s0014-5793(02)03416-6;
RA Grenier J.M., Wang L., Manji G.A., Huang W.-J., Al-Garawi A., Kelly R.,
RA Carlson A., Merriam S., Lora J.M., Briskin M., DiStefano P.S., Bertin J.;
RT "Functional screening of five PYPAF family members identifies PYPAF5 as a
RT novel regulator of NF-kappaB and caspase-1.";
RL FEBS Lett. 530:73-78(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT THR-144.
RA Miyamoto T.;
RL Submitted (FEB-2002) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3), AND VARIANT THR-144.
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), NUCLEOTIDE SEQUENCE
RP [LARGE SCALE MRNA] OF 436-994 (ISOFORM 2), AND VARIANTS ASP-383; GLN-390;
RP MET-774 AND LEU-925.
RC TISSUE=Placenta, and Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP FUNCTION IN INTERFERON PATHWAY.
RX PubMed=22388039; DOI=10.1038/ni.2239;
RA Cui J., Li Y., Zhu L., Liu D., Songyang Z., Wang H.Y., Wang R.F.;
RT "NLRP4 negatively regulates type I interferon signaling by targeting the
RT kinase TBK1 for degradation via the ubiquitin ligase DTX4.";
RL Nat. Immunol. 13:387-395(2012).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (2.28 ANGSTROMS) OF 1-110, AND PYRIN DOMAIN.
RX PubMed=22928810; DOI=10.1021/bi3007059;
RA Eibl C., Grigoriu S., Hessenberger M., Wenger J., Puehringer S.,
RA Pinheiro A.S., Wagner R.N., Proell M., Reed J.C., Page R., Diederichs K.,
RA Peti W.;
RT "Structural and functional analysis of the NLRP4 pyrin domain.";
RL Biochemistry 51:7330-7341(2012).
CC -!- FUNCTION: May be involved in inflammation and recognition of cytosolic
CC pathogen-associated molecular patterns (PAMPs) not intercepted by
CC membrane-bound receptors. Acts as a negative regulator of the type I
CC interferon signaling pathway by serving as an adapter to promote DTX4-
CC mediated ubiquitination of activated TBK1, and its subsequent
CC degradation. Suppresses NF-kappaB induction by the cytokines TNFA and
CC IL1B, suggesting that it operates at a point of convergence in these
CC two cytokine signaling pathways. {ECO:0000269|PubMed:12093792,
CC ECO:0000269|PubMed:22388039}.
CC -!- SUBUNIT: Interacts with CHUK/IKKA, inhibiting its kinase activity.
CC {ECO:0000269|PubMed:12093792}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Comment=Experimental confirmation may be lacking for some isoforms.;
CC Name=1;
CC IsoId=Q96MN2-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q96MN2-2; Sequence=VSP_003916, VSP_044007;
CC Name=3;
CC IsoId=Q96MN2-3; Sequence=VSP_003916;
CC -!- DOMAIN: The pyrin domain is sufficient for suppression of NF-kappaB
CC activity, it adopts a typical death domain fold, but in contrast to
CC several NLRP family pyrin domains it doesn't bind homotypically to the
CC ASC adapter, which supports the observation that NLRP4 has no effect on
CC IL1B activation.
CC -!- SIMILARITY: Belongs to the NLRP family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAL88672.1; Type=Erroneous termination; Note=Truncated C-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF442488; AAL35293.1; -; mRNA.
DR EMBL; AY072792; AAL68396.1; -; mRNA.
DR EMBL; AF479747; AAL87104.1; -; mRNA.
DR EMBL; AF482706; AAL88672.1; ALT_SEQ; mRNA.
DR EMBL; AK056688; BAB71254.1; -; mRNA.
DR EMBL; BC016443; AAH16443.1; -; mRNA.
DR EMBL; BC050326; AAH50326.1; -; mRNA.
DR CCDS; CCDS12936.1; -. [Q96MN2-1]
DR RefSeq; NP_604393.2; NM_134444.4. [Q96MN2-1]
DR PDB; 4EWI; X-ray; 2.28 A; A/B=1-110.
DR PDBsum; 4EWI; -.
DR AlphaFoldDB; Q96MN2; -.
DR SMR; Q96MN2; -.
DR BioGRID; 127102; 7.
DR DIP; DIP-60912N; -.
DR IntAct; Q96MN2; 2.
DR STRING; 9606.ENSP00000301295; -.
DR iPTMnet; Q96MN2; -.
DR PhosphoSitePlus; Q96MN2; -.
DR BioMuta; NLRP4; -.
DR DMDM; 148887404; -.
DR jPOST; Q96MN2; -.
DR MassIVE; Q96MN2; -.
DR PaxDb; Q96MN2; -.
DR PeptideAtlas; Q96MN2; -.
DR PRIDE; Q96MN2; -.
DR ProteomicsDB; 77378; -. [Q96MN2-1]
DR ProteomicsDB; 77379; -. [Q96MN2-2]
DR ProteomicsDB; 77380; -. [Q96MN2-3]
DR Antibodypedia; 33159; 150 antibodies from 24 providers.
DR DNASU; 147945; -.
DR Ensembl; ENST00000301295.11; ENSP00000301295.4; ENSG00000160505.16. [Q96MN2-1]
DR Ensembl; ENST00000587891.5; ENSP00000465463.1; ENSG00000160505.16. [Q96MN2-3]
DR GeneID; 147945; -.
DR KEGG; hsa:147945; -.
DR MANE-Select; ENST00000301295.11; ENSP00000301295.4; NM_134444.5; NP_604393.2.
DR UCSC; uc002qmd.5; human. [Q96MN2-1]
DR CTD; 147945; -.
DR DisGeNET; 147945; -.
DR GeneCards; NLRP4; -.
DR HGNC; HGNC:22943; NLRP4.
DR HPA; ENSG00000160505; Group enriched (lymphoid tissue, testis).
DR MIM; 609645; gene.
DR neXtProt; NX_Q96MN2; -.
DR OpenTargets; ENSG00000160505; -.
DR PharmGKB; PA162397947; -.
DR VEuPathDB; HostDB:ENSG00000160505; -.
DR eggNOG; KOG4308; Eukaryota.
DR GeneTree; ENSGT00940000162284; -.
DR HOGENOM; CLU_002274_2_1_1; -.
DR InParanoid; Q96MN2; -.
DR OMA; FYFCCQE; -.
DR PhylomeDB; Q96MN2; -.
DR PathwayCommons; Q96MN2; -.
DR Reactome; R-HSA-1606341; IRF3 mediated activation of type 1 IFN.
DR Reactome; R-HSA-3134975; Regulation of innate immune responses to cytosolic DNA.
DR Reactome; R-HSA-3270619; IRF3-mediated induction of type I IFN.
DR SignaLink; Q96MN2; -.
DR BioGRID-ORCS; 147945; 10 hits in 1066 CRISPR screens.
DR ChiTaRS; NLRP4; human.
DR GeneWiki; NLRP4; -.
DR GenomeRNAi; 147945; -.
DR Pharos; Q96MN2; Tbio.
DR PRO; PR:Q96MN2; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q96MN2; protein.
DR Bgee; ENSG00000160505; Expressed in secondary oocyte and 35 other tissues.
DR ExpressionAtlas; Q96MN2; baseline and differential.
DR Genevisible; Q96MN2; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0050727; P:regulation of inflammatory response; IBA:GO_Central.
DR Gene3D; 1.10.533.10; -; 1.
DR Gene3D; 3.40.50.300; -; 1.
DR Gene3D; 3.80.10.10; -; 1.
DR InterPro; IPR004020; DAPIN.
DR InterPro; IPR011029; DEATH-like_dom_sf.
DR InterPro; IPR001611; Leu-rich_rpt.
DR InterPro; IPR032675; LRR_dom_sf.
DR InterPro; IPR007111; NACHT_NTPase.
DR InterPro; IPR041267; NLRP_HD2.
DR InterPro; IPR041075; NOD2_WH.
DR InterPro; IPR027417; P-loop_NTPase.
DR Pfam; PF13516; LRR_6; 3.
DR Pfam; PF05729; NACHT; 1.
DR Pfam; PF17776; NLRC4_HD2; 1.
DR Pfam; PF17779; NOD2_WH; 1.
DR Pfam; PF02758; PYRIN; 1.
DR SMART; SM01289; PYRIN; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR PROSITE; PS50824; DAPIN; 1.
DR PROSITE; PS50837; NACHT; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Inflammatory response;
KW Leucine-rich repeat; Nucleotide-binding; Reference proteome; Repeat.
FT CHAIN 1..994
FT /note="NACHT, LRR and PYD domains-containing protein 4"
FT /id="PRO_0000080889"
FT DOMAIN 1..94
FT /note="Pyrin"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00061"
FT DOMAIN 149..472
FT /note="NACHT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00136"
FT REPEAT 637..660
FT /note="LRR 1"
FT REPEAT 698..721
FT /note="LRR 2"
FT REPEAT 722..745
FT /note="LRR 3"
FT REPEAT 750..777
FT /note="LRR 4"
FT REPEAT 806..833
FT /note="LRR 5"
FT REPEAT 863..886
FT /note="LRR 6"
FT REPEAT 920..943
FT /note="LRR 7"
FT REPEAT 949..972
FT /note="LRR 8"
FT BINDING 155..162
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00136"
FT VAR_SEQ 1..93
FT /note="MAASFFSDFGLMWYLEELKKEEFRKFKEHLKQMTLQLELKQIPWTEVKKASR
FT EELANLLIKHYEEQQAWNITLRIFQKMDRKDLCMKVMRERT -> MQECLTLWVFSPLA
FT LTDS (in isoform 3 and isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_003916"
FT VAR_SEQ 731..786
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_044007"
FT VARIANT 144
FT /note="A -> T (in dbSNP:rs441827)"
FT /evidence="ECO:0000269|PubMed:12093792,
FT ECO:0000269|PubMed:12387869, ECO:0000269|PubMed:12563287,
FT ECO:0000269|PubMed:14702039, ECO:0000269|Ref.4"
FT /id="VAR_024179"
FT VARIANT 383
FT /note="E -> D (in dbSNP:rs17857373)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_024827"
FT VARIANT 390
FT /note="P -> Q (in dbSNP:rs17857374)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_024828"
FT VARIANT 708
FT /note="R -> H (in dbSNP:rs12462372)"
FT /id="VAR_032764"
FT VARIANT 774
FT /note="L -> M (in dbSNP:rs17854614)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_024829"
FT VARIANT 925
FT /note="Q -> L (in dbSNP:rs302453)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_020007"
FT CONFLICT 55
FT /note="L -> P (in Ref. 4; AAL88672)"
FT /evidence="ECO:0000305"
FT CONFLICT 99
FT /note="Y -> H (in Ref. 4; AAL88672)"
FT /evidence="ECO:0000305"
FT CONFLICT 177
FT /note="I -> T (in Ref. 4; AAL88672)"
FT /evidence="ECO:0000305"
FT CONFLICT 209
FT /note="W -> R (in Ref. 4; AAL88672)"
FT /evidence="ECO:0000305"
FT CONFLICT 296
FT /note="I -> V (in Ref. 4; AAL88672)"
FT /evidence="ECO:0000305"
FT CONFLICT 720
FT /note="Y -> C (in Ref. 4; AAL88672)"
FT /evidence="ECO:0000305"
FT CONFLICT 957
FT /note="L -> P (in Ref. 4; AAL88672)"
FT /evidence="ECO:0000305"
FT HELIX 10..15
FT /evidence="ECO:0007829|PDB:4EWI"
FT HELIX 20..36
FT /evidence="ECO:0007829|PDB:4EWI"
FT HELIX 44..49
FT /evidence="ECO:0007829|PDB:4EWI"
FT HELIX 52..78
FT /evidence="ECO:0007829|PDB:4EWI"
FT HELIX 82..93
FT /evidence="ECO:0007829|PDB:4EWI"
SQ SEQUENCE 994 AA; 113415 MW; C2DDA1239274B2D1 CRC64;
MAASFFSDFG LMWYLEELKK EEFRKFKEHL KQMTLQLELK QIPWTEVKKA SREELANLLI
KHYEEQQAWN ITLRIFQKMD RKDLCMKVMR ERTGYTKTYQ AHAKQKFSRL WSSKSVTEIH
LYFEEEVKQE ECDHLDRLFA PKEAGKQPRT VIIQGPQGIG KTTLLMKLMM AWSDNKIFRD
RFLYTFYFCC RELRELPPTS LADLISREWP DPAAPITEIV SQPERLLFVI DSFEELQGGL
NEPDSDLCGD LMEKRPVQVL LSSLLRKKML PEASLLIAIK PVCPKELRDQ VTISEIYQPR
GFNESDRLVY FCCFFKDPKR AMEAFNLVRE SEQLFSICQI PLLCWILCTS LKQEMQKGKD
LALTCQSTTS VYSSFVFNLF TPEGAEGPTP QTQHQLKALC SLAAEGMWTD TFEFCEDDLR
RNGVVDADIP ALLGTKILLK YGERESSYVF LHVCIQEFCA ALFYLLKSHL DHPHPAVRCV
QELLVANFEK ARRAHWIFLG CFLTGLLNKK EQEKLDAFFG FQLSQEIKQQ IHQCLKSLGE
RGNPQGQVDS LAIFYCLFEM QDPAFVKQAV NLLQEANFHI IDNVDLVVSA YCLKYCSSLR
KLCFSVQNVF KKEDEHSSTS DYSLICWHHI CSVLTTSGHL RELQVQDSTL SESTFVTWCN
QLRHPSCRLQ KLGINNVSFS GQSVLLFEVL FYQPDLKYLS FTLTKLSRDD IRSLCDALNY
PAGNVKELAL VNCHLSPIDC EVLAGLLTNN KKLTYLNVSC NQLDTGVPLL CEALCSPDTV
LVYLMLAFCH LSEQCCEYIS EMLLRNKSVR YLDLSANVLK DEGLKTLCEA LKHPDCCLDS
LCLVKCFITA AGCEDLASAL ISNQNLKILQ IGCNEIGDVG VQLLCRALTH TDCRLEILGL
EECGLTSTCC KDLASVLTCS KTLQQLNLTL NTLDHTGVVV LCEALRHPEC ALQVLGLRKT
DFDEETQALL TAEEERNPNL TITDDCDTIT RVEI
