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Protein

Protein-arginine deiminase type-4

Gene

PADI4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Catalyzes the citrullination/deimination of arginine residues of proteins such as histones, thereby playing a key role in histone code and regulation of stem cell maintenance. Citrullinates histone H1 at 'Arg-54' (to form H1R54ci), histone H3 at 'Arg-2', 'Arg-8', 'Arg-17' and/or 'Arg-26' (to form H3R2ci, H3R8ci, H3R17ci, H3R26ci, respectively) and histone H4 at 'Arg-3' (to form H4R3ci). Acts as a key regulator of stem cell maintenance by mediating citrullination of histone H1: citrullination of 'Arg-54' of histone H1 (H1R54ci) results in H1 displacement from chromatin and global chromatin decondensation, thereby promoting pluripotency and stem cell maintenance. Promotes profound chromatin decondensation during the innate immune response to infection in neutrophils by mediating formation of H1R54ci. Citrullination of histone H3 prevents their methylation by CARM1 and HRMT1L2/PRMT1 and represses transcription. Citrullinates EP300/P300 at 'Arg-2142', which favors its interaction with NCOA2/GRIP1.6 Publications

Catalytic activityi

Protein L-arginine + H2O = protein L-citrulline + NH3.2 Publications

Cofactori

Ca2+3 PublicationsNote: Binds 5 Ca2+ ions per subunit.3 Publications

Activity regulationi

Strongly Inhibited by F-amidine and N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide (Cl-amidine). These inhibitors are however not specific to PADI4 and also inhibit other members of the family (PubMed:17002273). Incorporation of a carboxylate ortho to the backbone amide of Cl-amidine results in inhibitors with increased specificity for PADI4: N-alpha-(2-carboxyl)benzoyl-N5-(2-fluoro-1-iminoethyl)-L-ornithine amide (o-F-amidine) and N-alpha-(2-carboxyl)benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide (o-Cl-amidine) (PubMed:21882827). Strongly and specifically inhibited by Thr-Asp-F-amidine (TDFA); other members of the family are not inhibited (PubMed:22004374).3 Publications

Kineticsi

  1. KM=0.055 mM for fibrinogen1 Publication
  2. KM=0.064 mM for filaggrin1 Publication
  1. Vmax=33.2 µmol/h/mg enzyme toward fibrinogen1 Publication
  2. Vmax=8.0 µmol/h/mg enzyme toward filaggrin1 Publication

pH dependencei

Optimum pH is 6.5-9.0.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi153Calcium 13 Publications1
Metal bindingi155Calcium 13 Publications1
Metal bindingi155Calcium 23 Publications1
Metal bindingi157Calcium 13 Publications1
Metal bindingi157Calcium 23 Publications1
Metal bindingi165Calcium 13 Publications1
Metal bindingi165Calcium 3; via carbonyl oxygen3 Publications1
Metal bindingi168Calcium 33 Publications1
Metal bindingi170Calcium 3; via carbonyl oxygen3 Publications1
Metal bindingi176Calcium 13 Publications1
Metal bindingi179Calcium 13 Publications1
Metal bindingi179Calcium 23 Publications1
Binding sitei346TDFA Inhibitor1 Publication1
Metal bindingi349Calcium 43 Publications1
Active sitei3501 Publication1
Metal bindingi351Calcium 53 Publications1
Metal bindingi353Calcium 43 Publications1
Metal bindingi369Calcium 53 Publications1
Binding sitei369TDFA Inhibitor1 Publication1
Metal bindingi370Calcium 5; via carbonyl oxygen3 Publications1
Metal bindingi373Calcium 53 Publications1
Binding sitei374Substrate1
Binding sitei374TDFA Inhibitor1 Publication1
Metal bindingi388Calcium 23 Publications1
Metal bindingi407Calcium 4; via carbonyl oxygen3 Publications1
Metal bindingi410Calcium 4; via carbonyl oxygen3 Publications1
Metal bindingi411Calcium 43 Publications1
Active sitei4711 Publication1
Binding sitei471TDFA Inhibitor1 Publication1
Active sitei4731 Publication1
Binding sitei473TDFA Inhibitor1 Publication1
Binding sitei639Substrate; via carbonyl oxygen1
Active sitei6451 Publication1
Binding sitei645TDFA Inhibitor1 Publication1

GO - Molecular functioni

  • arginine binding Source: CAFA
  • arginine deiminase activity Source: UniProtKB
  • calcium ion binding Source: UniProtKB
  • protein-arginine deiminase activity Source: UniProtKB
  • protein homodimerization activity Source: CAFA

GO - Biological processi

Keywordsi

Molecular functionChromatin regulator, Hydrolase
Biological processImmunity, Innate immunity, Transcription, Transcription regulation
LigandCalcium, Metal-binding

Enzyme and pathway databases

BioCyciMetaCyc:HS08389-MONOMER
BRENDAi3.5.3.15 2681
ReactomeiR-HSA-3247509 Chromatin modifying enzymes

Names & Taxonomyi

Protein namesi
Recommended name:
Protein-arginine deiminase type-4 (EC:3.5.3.15)
Alternative name(s):
HL-60 PAD
Peptidylarginine deiminase IV
Protein-arginine deiminase type IV
Gene namesi
Name:PADI4
Synonyms:PAD4, PADI5, PDI5
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

EuPathDBiHostDB:ENSG00000159339.13
HGNCiHGNC:18368 PADI4
MIMi605347 gene
neXtProtiNX_Q9UM07

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, Nucleus

Pathology & Biotechi

Involvement in diseasei

Rheumatoid arthritis (RA)1 Publication
The gene represented in this entry may be involved in disease pathogenesis. The association to rheumatoid arthritis was initially thought to result from increased citrullination of target proteins (PubMed:12833157). However, variants that have been associated to rheumatoid arthritis (Ser-55, Ala-82 and Ala-112) do not affect the catalytic activity or the citrullination activity of PADI4, suggesting that these variants may affect the mRNA stability rather than the protein (PubMed:21245532).2 Publications
Disease descriptionAn inflammatory disease with autoimmune features and a complex genetic component. It primarily affects the joints and is characterized by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures.
See also OMIM:180300

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi346Q → A: Impaired binding of TDFA Inhibitor. 1 Publication1
Mutagenesisi374R → A: Strongly reduces enzymatic activity. 3 Publications1
Mutagenesisi374R → Q: Impaired binding of TDFA Inhibitor. 3 Publications1
Mutagenesisi639R → Q: Impaired binding of TDFA Inhibitor. 1 Publication1
Mutagenesisi645C → A: Abolishes enzymatic activity. 1 Publication1

Organism-specific databases

DisGeNETi23569
MalaCardsiPADI4
MIMi180300 phenotype
OpenTargetsiENSG00000159339
PharmGKBiPA32903

Chemistry databases

ChEMBLiCHEMBL6111
DrugBankiDB00207 Azithromycin
DB00254 Doxycycline
DB00155 L-Citrulline
DB07449 N-[(1S)-1-(AMINOCARBONYL)-4-(ETHANIMIDOYLAMINO)BUTYL]BENZAMIDE
DB01082 Streptomycin
DB00759 Tetracycline
GuidetoPHARMACOLOGYi2877

Polymorphism and mutation databases

BioMutaiPADI4
DMDMi296439260

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002200331 – 663Protein-arginine deiminase type-4Add BLAST663

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei205Citrulline1 Publication1
Modified residuei212Citrulline1 Publication1
Modified residuei218Citrulline1 Publication1
Modified residuei372Citrulline1 Publication1
Modified residuei374Citrulline1 Publication1
Modified residuei383Citrulline1 Publication1

Post-translational modificationi

Autocitrullination at Arg-372 and Arg-374 inactivates the enzyme.

Keywords - PTMi

Citrullination

Proteomic databases

MaxQBiQ9UM07
PaxDbiQ9UM07
PeptideAtlasiQ9UM07
PRIDEiQ9UM07
ProteomicsDBi85166

PTM databases

iPTMnetiQ9UM07
PhosphoSitePlusiQ9UM07

Expressioni

Tissue specificityi

Expressed in eosinophils and neutrophils, not expressed in peripheral monocytes or lymphocytes.1 Publication

Gene expression databases

BgeeiENSG00000159339 Expressed in 88 organ(s), highest expression level in blood
CleanExiHS_PADI4
ExpressionAtlasiQ9UM07 baseline and differential
GenevisibleiQ9UM07 HS

Organism-specific databases

HPAiHPA017007
HPA042825

Interactioni

Binary interactionsi

WithEntry#Exp.IntActNotes
ANXA4Q6LES25EBI-1042511,EBI-10250835

GO - Molecular functioni

Protein-protein interaction databases

BioGridi117111, 13 interactors
DIPiDIP-50397N
IntActiQ9UM07, 4 interactors
STRINGi9606.ENSP00000364597

Chemistry databases

BindingDBiQ9UM07

Structurei

Secondary structure

1663
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

DisProtiDP00321
ProteinModelPortaliQ9UM07
SMRiQ9UM07
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ9UM07

Family & Domainsi

Sequence similaritiesi

Belongs to the protein arginine deiminase family.Curated

Phylogenomic databases

eggNOGiENOG410IF3F Eukaryota
ENOG410ZKF3 LUCA
GeneTreeiENSGT00390000008680
HOGENOMiHOG000220908
HOVERGENiHBG053016
InParanoidiQ9UM07
KOiK01481
OMAiRVFQATR
OrthoDBiEOG091G02QG
PhylomeDBiQ9UM07
TreeFamiTF331952

Family and domain databases

Gene3Di2.60.40.1700, 1 hit
2.60.40.1860, 1 hit
InterProiView protein in InterPro
IPR008972 Cupredoxin
IPR004303 PAD
IPR013530 PAD_C
IPR036556 PAD_central_sf
IPR013732 PAD_N
IPR038685 PAD_N_sf
IPR013733 Prot_Arg_deaminase_cen_dom
PANTHERiPTHR10837 PTHR10837, 1 hit
PfamiView protein in Pfam
PF03068 PAD, 1 hit
PF08527 PAD_M, 1 hit
PF08526 PAD_N, 1 hit
PIRSFiPIRSF001247 Protein-arginine_deiminase, 1 hit
SUPFAMiSSF110083 SSF110083, 1 hit
SSF49503 SSF49503, 1 hit

Sequence (1+)i

Sequence statusi: Complete.

This entry has 1 described isoform and 1 potential isoform that is computationally mapped.Show allAlign All

Q9UM07-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MAQGTLIRVT PEQPTHAVCV LGTLTQLDIC SSAPEDCTSF SINASPGVVV
60 70 80 90 100
DIAHGPPAKK KSTGSSTWPL DPGVEVTLTM KVASGSTGDQ KVQISYYGPK
110 120 130 140 150
TPPVKALLYL TGVEISLCAD ITRTGKVKPT RAVKDQRTWT WGPCGQGAIL
160 170 180 190 200
LVNCDRDNLE SSAMDCEDDE VLDSEDLQDM SLMTLSTKTP KDFFTNHTLV
210 220 230 240 250
LHVARSEMDK VRVFQATRGK LSSKCSVVLG PKWPSHYLMV PGGKHNMDFY
260 270 280 290 300
VEALAFPDTD FPGLITLTIS LLDTSNLELP EAVVFQDSVV FRVAPWIMTP
310 320 330 340 350
NTQPPQEVYA CSIFENEDFL KSVTTLAMKA KCKLTICPEE ENMDDQWMQD
360 370 380 390 400
EMEIGYIQAP HKTLPVVFDS PRNRGLKEFP IKRVMGPDFG YVTRGPQTGG
410 420 430 440 450
ISGLDSFGNL EVSPPVTVRG KEYPLGRILF GDSCYPSNDS RQMHQALQDF
460 470 480 490 500
LSAQQVQAPV KLYSDWLSVG HVDEFLSFVP APDRKGFRLL LASPRSCYKL
510 520 530 540 550
FQEQQNEGHG EALLFEGIKK KKQQKIKNIL SNKTLREHNS FVERCIDWNR
560 570 580 590 600
ELLKRELGLA ESDIIDIPQL FKLKEFSKAE AFFPNMVNML VLGKHLGIPK
610 620 630 640 650
PFGPVINGRC CLEEKVCSLL EPLGLQCTFI NDFFTYHIRH GEVHCGTNVR
660
RKPFSFKWWN MVP
Length:663
Mass (Da):74,079
Last modified:May 18, 2010 - v2
Checksum:i79D7AF7B3D307A3B
GO

Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
B1AQ67B1AQ67_HUMAN
Protein-arginine deiminase type-4
PADI4
127Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti149I → V in BAF83196 (PubMed:14702039).Curated1
Sequence conflicti247M → T in BAG37357 (PubMed:14702039).Curated1
Sequence conflicti657K → E in BAF83196 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0535608R → H. Corresponds to variant dbSNP:rs35381732Ensembl.1
Natural variantiVAR_02063955G → S Does not affect catalytic activity. 3 PublicationsCorresponds to variant dbSNP:rs11203366Ensembl.1
Natural variantiVAR_05356179T → M. Corresponds to variant dbSNP:rs35809521Ensembl.1
Natural variantiVAR_02064082V → A Does not affect catalytic activity. 3 PublicationsCorresponds to variant dbSNP:rs11203367Ensembl.1
Natural variantiVAR_02740189D → N1 PublicationCorresponds to variant dbSNP:rs143187209Ensembl.1
Natural variantiVAR_027402102P → T1 PublicationCorresponds to variant dbSNP:rs34309058Ensembl.1
Natural variantiVAR_020641112G → A Does not affect catalytic activity. 3 PublicationsCorresponds to variant dbSNP:rs874881Ensembl.1
Natural variantiVAR_027403131R → T1 PublicationCorresponds to variant dbSNP:rs12733102Ensembl.1
Natural variantiVAR_027404164M → T. Corresponds to variant dbSNP:rs11588132Ensembl.1
Natural variantiVAR_053562260D → N. Corresponds to variant dbSNP:rs35903413Ensembl.1
Natural variantiVAR_020642275S → F1 PublicationCorresponds to variant dbSNP:rs1748020Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB017919 mRNA Translation: BAA84542.1
AJ549502 Genomic DNA Translation: CAE47743.1
AK290507 mRNA Translation: BAF83196.1
AK314839 mRNA Translation: BAG37357.1
AC004824 Genomic DNA No translation available.
AL590644 Genomic DNA No translation available.
BC025718 mRNA Translation: AAH25718.1
CCDSiCCDS180.1
RefSeqiNP_036519.2, NM_012387.2
UniGeneiHs.522969

Genome annotation databases

EnsembliENST00000375448; ENSP00000364597; ENSG00000159339
ENST00000628229; ENSP00000487021; ENSG00000280908
GeneIDi23569
KEGGihsa:23569
UCSCiuc001baj.3 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB017919 mRNA Translation: BAA84542.1
AJ549502 Genomic DNA Translation: CAE47743.1
AK290507 mRNA Translation: BAF83196.1
AK314839 mRNA Translation: BAG37357.1
AC004824 Genomic DNA No translation available.
AL590644 Genomic DNA No translation available.
BC025718 mRNA Translation: AAH25718.1
CCDSiCCDS180.1
RefSeqiNP_036519.2, NM_012387.2
UniGeneiHs.522969

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1WD8X-ray2.80A1-663[»]
1WD9X-ray2.60A1-663[»]
1WDAX-ray2.30A1-663[»]
2DEWX-ray2.10X1-663[»]
2DEXX-ray2.10X1-663[»]
2DEYX-ray2.25X1-663[»]
2DW5X-ray2.30A1-663[»]
3APMX-ray2.50A1-663[»]
3APNX-ray2.70A1-663[»]
3B1TX-ray2.50A1-663[»]
3B1UX-ray2.10A1-663[»]
4DKTX-ray2.98A1-663[»]
4X8CX-ray3.10A1-663[»]
4X8GX-ray3.29A1-663[»]
5N0MX-ray2.18A1-663[»]
5N0YX-ray2.23A1-663[»]
5N0ZX-ray2.52A1-663[»]
5N1BX-ray2.90A1-663[»]
DisProtiDP00321
ProteinModelPortaliQ9UM07
SMRiQ9UM07
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi117111, 13 interactors
DIPiDIP-50397N
IntActiQ9UM07, 4 interactors
STRINGi9606.ENSP00000364597

Chemistry databases

BindingDBiQ9UM07
ChEMBLiCHEMBL6111
DrugBankiDB00207 Azithromycin
DB00254 Doxycycline
DB00155 L-Citrulline
DB07449 N-[(1S)-1-(AMINOCARBONYL)-4-(ETHANIMIDOYLAMINO)BUTYL]BENZAMIDE
DB01082 Streptomycin
DB00759 Tetracycline
GuidetoPHARMACOLOGYi2877

PTM databases

iPTMnetiQ9UM07
PhosphoSitePlusiQ9UM07

Polymorphism and mutation databases

BioMutaiPADI4
DMDMi296439260

Proteomic databases

MaxQBiQ9UM07
PaxDbiQ9UM07
PeptideAtlasiQ9UM07
PRIDEiQ9UM07
ProteomicsDBi85166

Protocols and materials databases

DNASUi23569
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000375448; ENSP00000364597; ENSG00000159339
ENST00000628229; ENSP00000487021; ENSG00000280908
GeneIDi23569
KEGGihsa:23569
UCSCiuc001baj.3 human

Organism-specific databases

CTDi23569
DisGeNETi23569
EuPathDBiHostDB:ENSG00000159339.13
GeneCardsiPADI4
H-InvDBiHIX0000182
HGNCiHGNC:18368 PADI4
HPAiHPA017007
HPA042825
MalaCardsiPADI4
MIMi180300 phenotype
605347 gene
neXtProtiNX_Q9UM07
OpenTargetsiENSG00000159339
PharmGKBiPA32903
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410IF3F Eukaryota
ENOG410ZKF3 LUCA
GeneTreeiENSGT00390000008680
HOGENOMiHOG000220908
HOVERGENiHBG053016
InParanoidiQ9UM07
KOiK01481
OMAiRVFQATR
OrthoDBiEOG091G02QG
PhylomeDBiQ9UM07
TreeFamiTF331952

Enzyme and pathway databases

BioCyciMetaCyc:HS08389-MONOMER
BRENDAi3.5.3.15 2681
ReactomeiR-HSA-3247509 Chromatin modifying enzymes

Miscellaneous databases

ChiTaRSiPADI4 human
EvolutionaryTraceiQ9UM07
GeneWikiiPADI4
GenomeRNAii23569
PROiPR:Q9UM07
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000159339 Expressed in 88 organ(s), highest expression level in blood
CleanExiHS_PADI4
ExpressionAtlasiQ9UM07 baseline and differential
GenevisibleiQ9UM07 HS

Family and domain databases

Gene3Di2.60.40.1700, 1 hit
2.60.40.1860, 1 hit
InterProiView protein in InterPro
IPR008972 Cupredoxin
IPR004303 PAD
IPR013530 PAD_C
IPR036556 PAD_central_sf
IPR013732 PAD_N
IPR038685 PAD_N_sf
IPR013733 Prot_Arg_deaminase_cen_dom
PANTHERiPTHR10837 PTHR10837, 1 hit
PfamiView protein in Pfam
PF03068 PAD, 1 hit
PF08527 PAD_M, 1 hit
PF08526 PAD_N, 1 hit
PIRSFiPIRSF001247 Protein-arginine_deiminase, 1 hit
SUPFAMiSSF110083 SSF110083, 1 hit
SSF49503 SSF49503, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiPADI4_HUMAN
AccessioniPrimary (citable) accession number: Q9UM07
Secondary accession number(s): A8K392
, B2RBW0, Q5VTZ8, Q70SX4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: January 11, 2001
Last sequence update: May 18, 2010
Last modified: November 7, 2018
This is version 169 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  3. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  4. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  5. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  6. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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