PADI4_MOUSE
ID PADI4_MOUSE Reviewed; 666 AA.
AC Q9Z183; A2AMU3; Q75WC7;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 3.
DT 03-AUG-2022, entry version 151.
DE RecName: Full=Protein-arginine deiminase type-4;
DE EC=3.5.3.15 {ECO:0000269|PubMed:15339660};
DE AltName: Full=Peptidylarginine deiminase IV;
DE AltName: Full=Protein-arginine deiminase type IV;
GN Name=Padi4; Synonyms=Pad4, Pdi4;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Epidermis;
RX PubMed=10092850; DOI=10.1046/j.1432-1327.1999.00083.x;
RA Rusd A.A., Ikejiri Y., Ono H., Yonekawa T., Shiraiwa M., Kawada A.,
RA Takahara H.;
RT "Molecular cloning of cDNAs of mouse peptidylarginine deiminase type I,
RT type III and type IV, and the expression pattern of type I in mouse.";
RL Eur. J. Biochem. 259:660-669(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=129/SvJ;
RX PubMed=15087120; DOI=10.1016/j.gene.2003.12.038;
RA Chavanas S., Mechin M.-C., Takahara H., Kawada A., Nachat R., Serre G.,
RA Simon M.;
RT "Comparative analysis of the mouse and human peptidylarginine deiminase
RT gene clusters reveals highly conserved non-coding segments and a new human
RT gene, PADI6.";
RL Gene 330:19-27(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [4]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=15339660; DOI=10.1016/j.cell.2004.08.020;
RA Cuthbert G.L., Daujat S., Snowden A.W., Erdjument-Bromage H., Hagiwara T.,
RA Yamada M., Schneider R., Gregory P.D., Tempst P., Bannister A.J.,
RA Kouzarides T.;
RT "Histone deimination antagonizes arginine methylation.";
RL Cell 118:545-553(2004).
RN [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=20733033; DOI=10.1084/jem.20100239;
RA Li P., Li M., Lindberg M.R., Kennett M.J., Xiong N., Wang Y.;
RT "PAD4 is essential for antibacterial innate immunity mediated by neutrophil
RT extracellular traps.";
RL J. Exp. Med. 207:1853-1862(2010).
RN [6]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=23650392; DOI=10.1073/pnas.1301059110;
RA Martinod K., Demers M., Fuchs T.A., Wong S.L., Brill A., Gallant M., Hu J.,
RA Wang Y., Wagner D.D.;
RT "Neutrophil histone modification by peptidylarginine deiminase 4 is
RT critical for deep vein thrombosis in mice.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:8674-8679(2013).
RN [7]
RP FUNCTION, TISSUE SPECIFICITY, AND ACTIVITY REGULATION.
RX PubMed=24463520; DOI=10.1038/nature12942;
RA Christophorou M.A., Castelo-Branco G., Halley-Stott R.P., Oliveira C.S.,
RA Loos R., Radzisheuskaya A., Mowen K.A., Bertone P., Silva J.C.,
RA Zernicka-Goetz M., Nielsen M.L., Gurdon J.B., Kouzarides T.;
RT "Citrullination regulates pluripotency and histone H1 binding to
RT chromatin.";
RL Nature 507:104-108(2014).
RN [8]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=32528174; DOI=10.1038/s41586-020-2394-6;
RA Yang L., Liu Q., Zhang X., Liu X., Zhou B., Chen J., Huang D., Li J.,
RA Li H., Chen F., Liu J., Xing Y., Chen X., Su S., Song E.;
RT "DNA of neutrophil extracellular traps promotes cancer metastasis via
RT CCDC25.";
RL Nature 583:133-138(2020).
CC -!- FUNCTION: Catalyzes the citrullination/deimination of arginine residues
CC of proteins such as histones, thereby playing a key role in histone
CC code and regulation of stem cell maintenance (PubMed:15339660,
CC PubMed:32528174). Citrullinates histone H1 at 'Arg-54' (to form
CC H1R54ci), histone H3 at 'Arg-2', 'Arg-8', 'Arg-17' and/or 'Arg-26' (to
CC form H3R2ci, H3R8ci, H3R17ci, H3R26ci, respectively) and histone H4 at
CC 'Arg-3' (to form H4R3ci) (PubMed:15339660). Acts as a key regulator of
CC stem cell maintenance by mediating citrullination of histone H1:
CC citrullination of 'Arg-54' of histone H1 (H1R54ci) results in H1
CC displacement from chromatin and global chromatin decondensation,
CC thereby promoting pluripotency and stem cell maintenance
CC (PubMed:24463520, PubMed:32528174). Promotes profound chromatin
CC decondensation during the innate immune response to infection in
CC neutrophils by mediating formation of H1R54ci (PubMed:20733033,
CC PubMed:23650392). Required for the formation of neutrophil
CC extracellular traps (NETs); NETs are mainly composed of DNA fibers and
CC are released by neutrophils to bind pathogens during inflammation
CC (PubMed:20733033, PubMed:32528174). Citrullination of histone H3
CC prevents their methylation by CARM1 and HRMT1L2/PRMT1 and represses
CC transcription (By similarity). Citrullinates EP300/P300 at 'Arg-2142',
CC which favors its interaction with NCOA2/GRIP1 (By similarity).
CC {ECO:0000250|UniProtKB:Q9UM07, ECO:0000269|PubMed:15339660,
CC ECO:0000269|PubMed:20733033, ECO:0000269|PubMed:23650392,
CC ECO:0000269|PubMed:24463520, ECO:0000269|PubMed:32528174}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + L-arginyl-[protein] = L-citrullyl-[protein] + NH4(+);
CC Xref=Rhea:RHEA:18089, Rhea:RHEA-COMP:10532, Rhea:RHEA-COMP:10588,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:28938, ChEBI:CHEBI:29965,
CC ChEBI:CHEBI:83397; EC=3.5.3.15;
CC Evidence={ECO:0000269|PubMed:15339660};
CC -!- COFACTOR:
CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108;
CC Evidence={ECO:0000250|UniProtKB:Q9UM07};
CC Note=Binds 5 Ca(2+) ions per subunit. {ECO:0000250|UniProtKB:Q9UM07};
CC -!- ACTIVITY REGULATION: Strongly Inhibited by F-amidine and N-alpha-
CC benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide (Cl-amidine).
CC These inhibitors are however not specific to PADI4 and also inhibit
CC other members of the family. {ECO:0000269|PubMed:24463520}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9UM07}. Nucleus
CC {ECO:0000250|UniProtKB:Q9UM07}. Cytoplasmic granule
CC {ECO:0000250|UniProtKB:Q9UM07}. Note=Cytoplasmic granules of
CC eosinophils and neutrophils. {ECO:0000250|UniProtKB:Q9UM07}.
CC -!- TISSUE SPECIFICITY: Expressed in pluripotent embryonic stem and induced
CC pluripotent stem cells but not multipotent neural stem cells.
CC {ECO:0000269|PubMed:24463520}.
CC -!- PTM: Autocitrullination at Arg-372 and Arg-374 inactivates the enzyme.
CC {ECO:0000250|UniProtKB:Q9UM07}.
CC -!- DISRUPTION PHENOTYPE: Mice survive to adulthood and do not display
CC detectable physical abnormality (PubMed:20733033). However, mice were
CC born at a rate lower than predicted by the Mendelian ratio and display
CC defects in innate immune response (PubMed:20733033). Impaired formation
CC of neutrophil extracellular traps (NETs) (PubMed:20733033,
CC PubMed:32528174). Mice are more susceptible to bacterial infection:
CC neutrophils cannot form NETs after stimulation with chemokines or
CC incubation with bacteria, and are deficient in bacterial killing by
CC NETs (PubMed:20733033). Less than 10% of deficient mice produce a
CC thrombus 48 hours after inferior vena cava stenosis whereas 90% of
CC wild-type mice do (PubMed:23650392). {ECO:0000269|PubMed:20733033,
CC ECO:0000269|PubMed:23650392, ECO:0000269|PubMed:32528174}.
CC -!- SIMILARITY: Belongs to the protein arginine deiminase family.
CC {ECO:0000305}.
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DR EMBL; AB013850; BAA34246.1; -; mRNA.
DR EMBL; AB121692; BAD16627.1; -; Genomic_DNA.
DR EMBL; AL807805; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS18854.1; -.
DR RefSeq; NP_035191.2; NM_011061.2.
DR PDB; 6MKD; X-ray; 3.20 A; D=93-105.
DR PDB; 6MKR; X-ray; 3.35 A; D=93-105.
DR PDB; 6MNG; X-ray; 2.66 A; D=93-105.
DR PDB; 6MNM; X-ray; 3.10 A; D=93-105.
DR PDB; 6MNN; X-ray; 2.83 A; D=93-105.
DR PDB; 6MNO; X-ray; 2.90 A; D=93-105.
DR PDBsum; 6MKD; -.
DR PDBsum; 6MKR; -.
DR PDBsum; 6MNG; -.
DR PDBsum; 6MNM; -.
DR PDBsum; 6MNN; -.
DR PDBsum; 6MNO; -.
DR AlphaFoldDB; Q9Z183; -.
DR SMR; Q9Z183; -.
DR STRING; 10090.ENSMUSP00000026381; -.
DR BindingDB; Q9Z183; -.
DR ChEMBL; CHEMBL3407322; -.
DR iPTMnet; Q9Z183; -.
DR PhosphoSitePlus; Q9Z183; -.
DR EPD; Q9Z183; -.
DR MaxQB; Q9Z183; -.
DR PaxDb; Q9Z183; -.
DR PeptideAtlas; Q9Z183; -.
DR PRIDE; Q9Z183; -.
DR ProteomicsDB; 287936; -.
DR ABCD; Q9Z183; 10 sequenced antibodies.
DR Antibodypedia; 1465; 528 antibodies from 38 providers.
DR DNASU; 18602; -.
DR Ensembl; ENSMUST00000026381; ENSMUSP00000026381; ENSMUSG00000025330.
DR GeneID; 18602; -.
DR KEGG; mmu:18602; -.
DR UCSC; uc008vne.2; mouse.
DR CTD; 23569; -.
DR MGI; MGI:1338898; Padi4.
DR VEuPathDB; HostDB:ENSMUSG00000025330; -.
DR eggNOG; ENOG502QVJA; Eukaryota.
DR GeneTree; ENSGT00940000153217; -.
DR HOGENOM; CLU_021911_0_0_1; -.
DR InParanoid; Q9Z183; -.
DR OMA; RVFQATR; -.
DR OrthoDB; 787070at2759; -.
DR PhylomeDB; Q9Z183; -.
DR TreeFam; TF331952; -.
DR BRENDA; 3.5.3.15; 3474.
DR Reactome; R-MMU-3247509; Chromatin modifying enzymes.
DR BioGRID-ORCS; 18602; 8 hits in 78 CRISPR screens.
DR PRO; PR:Q9Z183; -.
DR Proteomes; UP000000589; Chromosome 4.
DR RNAct; Q9Z183; protein.
DR Bgee; ENSMUSG00000025330; Expressed in granulocyte and 49 other tissues.
DR Genevisible; Q9Z183; MM.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; ISO:MGI.
DR GO; GO:0034618; F:arginine binding; ISO:MGI.
DR GO; GO:0005509; F:calcium ion binding; ISS:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0004668; F:protein-arginine deiminase activity; IDA:UniProtKB.
DR GO; GO:0006325; P:chromatin organization; IMP:UniProtKB.
DR GO; GO:0006338; P:chromatin remodeling; IMP:UniProtKB.
DR GO; GO:0036414; P:histone citrullination; IDA:UniProtKB.
DR GO; GO:0036413; P:histone H3-R26 citrullination; ISS:UniProtKB.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0006334; P:nucleosome assembly; IMP:UniProtKB.
DR GO; GO:0043687; P:post-translational protein modification; IEA:Ensembl.
DR GO; GO:0018101; P:protein citrullination; ISO:MGI.
DR GO; GO:0019827; P:stem cell population maintenance; IMP:UniProtKB.
DR Gene3D; 2.60.40.1700; -; 1.
DR Gene3D; 2.60.40.1860; -; 1.
DR InterPro; IPR008972; Cupredoxin.
DR InterPro; IPR004303; PAD.
DR InterPro; IPR013530; PAD_C.
DR InterPro; IPR036556; PAD_central_sf.
DR InterPro; IPR013732; PAD_N.
DR InterPro; IPR038685; PAD_N_sf.
DR InterPro; IPR013733; Prot_Arg_deaminase_cen_dom.
DR PANTHER; PTHR10837; PTHR10837; 1.
DR Pfam; PF03068; PAD; 1.
DR Pfam; PF08527; PAD_M; 1.
DR Pfam; PF08526; PAD_N; 1.
DR PIRSF; PIRSF001247; Protein-arginine_deiminase; 1.
DR SUPFAM; SSF110083; SSF110083; 1.
DR SUPFAM; SSF49503; SSF49503; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Calcium; Chromatin regulator; Citrullination; Cytoplasm;
KW Hydrolase; Immunity; Innate immunity; Metal-binding; Nucleus;
KW Reference proteome; Transcription; Transcription regulation.
FT CHAIN 1..666
FT /note="Protein-arginine deiminase type-4"
FT /id="PRO_0000220034"
FT ACT_SITE 350
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT ACT_SITE 471
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT ACT_SITE 473
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT ACT_SITE 648
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT BINDING 153
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT BINDING 155
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT BINDING 155
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT BINDING 165
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT BINDING 165
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT BINDING 168
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT BINDING 176
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT BINDING 179
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT BINDING 179
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT BINDING 349
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="4"
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT BINDING 351
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="5"
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT BINDING 353
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="4"
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT BINDING 369
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="5"
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT BINDING 370
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="5"
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT BINDING 374
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT BINDING 407
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="4"
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT BINDING 410
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="4"
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT BINDING 411
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="4"
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT MOD_RES 212
FT /note="Citrulline"
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT MOD_RES 218
FT /note="Citrulline"
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT MOD_RES 372
FT /note="Citrulline"
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT MOD_RES 374
FT /note="Citrulline"
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT MOD_RES 383
FT /note="Citrulline"
FT /evidence="ECO:0000250|UniProtKB:Q9UM07"
FT CONFLICT 41
FT /note="G -> S (in Ref. 1; BAA34246)"
FT /evidence="ECO:0000305"
FT CONFLICT 90
FT /note="E -> Q (in Ref. 1; BAA34246)"
FT /evidence="ECO:0000305"
FT CONFLICT 99
FT /note="P -> L (in Ref. 2; BAD16627)"
FT /evidence="ECO:0000305"
FT CONFLICT 131
FT /note="Q -> P (in Ref. 1; BAA34246)"
FT /evidence="ECO:0000305"
FT CONFLICT 210
FT /note="R -> K (in Ref. 1; BAA34246)"
FT /evidence="ECO:0000305"
FT CONFLICT 222
FT /note="P -> L (in Ref. 1; BAA34246)"
FT /evidence="ECO:0000305"
FT CONFLICT 481
FT /note="A -> V (in Ref. 1; BAA34246)"
FT /evidence="ECO:0000305"
FT CONFLICT 573
FT /note="A -> V (in Ref. 1; BAA34246)"
FT /evidence="ECO:0000305"
FT CONFLICT 612
FT /note="H -> R (in Ref. 1; BAA34246)"
FT /evidence="ECO:0000305"
FT CONFLICT 655..656
FT /note="KP -> T (in Ref. 2; BAD16627)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 666 AA; 74415 MW; F25B7A7B69285C32 CRC64;
MAQGAVIHVA PEQPTHAVCV VGTATPLDVR GSAPKGYTTF GITASPGVIV DVIHGPPVKK
STMGASKWPL DPELEVTLQV KAASSRTDDE KVRVSYYGPK TSPVQALIYI TGVELSLSAD
VTRTGRVKPA QAGKDQSTWT WGPGGRGAIL LVNCDKEDPQ ASGMDFEDDK ILDNKDLQDM
SPMTLSTKTP KDFFEKYQLV LEVPKAKMNR VRVFRATRGK LPSRYKVALG PQQFSYCLEL
PGGQHSTDFY VEGLAFPDAD FKGLIPLTIS LLDKSNPELP EALVFQDSVT FRVAPWIMTP
NTQPPQEVYV CRVSDNEDFL KSLATLTKKA KCKLTVCPEE ENIDDQWMQD EMEIGYIQAP
HKTLPVVFDS PRDRGLKDFP VKRVMGPNFG YVTRKLYMSE LTGLDAFGNL EVSPPVTVRG
KEYPLGRILI GNSGYSSSES RDMHQALQDF LSAQQVQAPV RLFSDWLFVG HVDEFLSFVP
ARDKQGFRLL LSSPRACYQL FQELQSQGHG EATLFEGLKR KRQTINEILS NKKLRDQNAY
VESCIDWNRA VLKRELGLAE GDIIDIPQLF KLAGNSRGNS KAQAFFPNMV NMLVLGKYLG
IPKPFGPIID GHCCLEEEVR SHLEPLGLHC TFINDFYTYH VYNGEVHCGT NVRRKPFTFK
WWHMVP
