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 24-JAN-2024, entry version 159. 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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; 10090-ENSMUSP00000026381; -. DR PeptideAtlas; Q9Z183; -. DR ProteomicsDB; 287936; -. DR ABCD; Q9Z183; 10 sequenced antibodies. DR Antibodypedia; 1465; 578 antibodies from 38 providers. DR DNASU; 18602; -. DR Ensembl; ENSMUST00000026381.7; ENSMUSP00000026381.7; ENSMUSG00000025330.7. DR GeneID; 18602; -. DR KEGG; mmu:18602; -. DR UCSC; uc008vne.2; mouse. DR AGR; MGI:1338898; -. 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; DQRTWTW; -. DR OrthoDB; 3956477at2759; -. 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 84 CRISPR screens. DR PRO; PR:Q9Z183; -. DR Proteomes; UP000000589; Chromosome 4. DR RNAct; Q9Z183; Protein. DR Bgee; ENSMUSG00000025330; Expressed in granulocyte and 51 other cell types or tissues. 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:0005509; F:calcium ion binding; ISS:UniProtKB. DR GO; GO:0140794; F:histone arginine deiminase activity; ISO:MGI. DR GO; GO:0140797; F:histone H3R17 arginine deiminase activity; ISO:MGI. DR GO; GO:0140795; F:histone H3R2 arginine deiminase activity; ISO:MGI. DR GO; GO:0140798; F:histone H3R26 arginine deiminase activity; ISO:MGI. DR GO; GO:0140796; F:histone H3R8 arginine deiminase activity; ISO:MGI. 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: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; ISO:MGI. DR GO; GO:0019827; P:stem cell population maintenance; IMP:UniProtKB. DR CDD; cd04214; PAD_N; 1. DR Gene3D; 2.60.40.1700; Protein-arginine deiminase, central domain; 1. DR Gene3D; 2.60.40.1860; Protein-arginine deiminase, N-terminal domain; 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; PEPTIDYLARGININE DEIMINASE; 1. DR PANTHER; PTHR10837:SF3; PROTEIN-ARGININE DEIMINASE TYPE-4; 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; SSF49503; Cupredoxins; 1. DR SUPFAM; SSF55909; Pentein; 1. DR SUPFAM; SSF110083; Peptidylarginine deiminase Pad4, middle domain; 1. DR Genevisible; Q9Z183; MM. 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 //