UniProt functional annotation for Q9UM07



	UniProt functional annotation for Q9UM07

UniProt code: Q9UM07.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: 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 (PubMed:15339660, PubMed:15345777, PubMed:16567635, PubMed:21245532). 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) (PubMed:15339660, PubMed:15345777, PubMed:16567635, PubMed:21245532). 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 (PubMed:15339660, PubMed:15345777, PubMed:16567635, PubMed:21245532). Promotes profound chromatin decondensation during the innate immune response to infection in neutrophils by mediating formation of H1R54ci (PubMed:18209087). Required for the formation of neutrophil extracellular traps (NETs); NETs are mainly composed of DNA fibers and are released by neutrophils to bind pathogens during inflammation (By similarity). Citrullination of histone H3 prevents their methylation by CARM1 and HRMT1L2/PRMT1 and represses transcription (PubMed:15345777). Citrullinates EP300/P300 at 'Arg- 2142', which favors its interaction with NCOA2/GRIP1 (PubMed:15731352). {ECO:0000250|UniProtKB:Q9Z183, ECO:0000269|PubMed:15339660, ECO:0000269|PubMed:15345777, ECO:0000269|PubMed:15731352, ECO:0000269|PubMed:16567635, ECO:0000269|PubMed:18209087, ECO:0000269|PubMed:21245532}.

Catalytic activity: Reaction=H2O + L-arginyl-[protein] = L-citrullyl-[protein] + NH4(+); Xref=Rhea:RHEA:18089, Rhea:RHEA-COMP:10532, Rhea:RHEA-COMP:10588, ChEBI:CHEBI:15377, ChEBI:CHEBI:28938, ChEBI:CHEBI:29965, ChEBI:CHEBI:83397; EC=3.5.3.15; Evidence={ECO:0000269|PubMed:16567635, ECO:0000269|PubMed:21245532};

Cofactor: Name=Ca(2+); Xref=ChEBI:CHEBI:29108; Evidence={ECO:0000269|PubMed:15629448, ECO:0000269|PubMed:16567635, ECO:0000269|PubMed:17002273}; Note=Binds 5 Ca(2+) ions per subunit. {ECO:0000269|PubMed:15629448, ECO:0000269|PubMed:16567635, ECO:0000269|PubMed:17002273};

Activity regulation: 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-N(5)-(2-fluoro-1-iminoethyl)-L-ornithine amide (o-F- amidine) and N-alpha-(2-carboxyl)benzoyl-N(5)-(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). {ECO:0000269|PubMed:17002273, ECO:0000269|PubMed:21882827, ECO:0000269|PubMed:22004374}.

Biophysicochemical properties: Kinetic parameters: KM=0.055 mM for fibrinogen {ECO:0000269|PubMed:15629448}; KM=0.064 mM for filaggrin {ECO:0000269|PubMed:15629448}; Vmax=33.2 umol/h/mg enzyme toward fibrinogen {ECO:0000269|PubMed:15629448}; Vmax=8.0 umol/h/mg enzyme toward filaggrin {ECO:0000269|PubMed:15629448}; pH dependence: Optimum pH is 6.5-9.0. {ECO:0000269|PubMed:15629448};

Subcellular location: Cytoplasm {ECO:0000269|PubMed:15629448}. Nucleus {ECO:0000269|PubMed:15629448}. Cytoplasmic granule {ECO:0000269|PubMed:11435484}. Note=Cytoplasmic granules of eosinophils and neutrophils. {ECO:0000269|PubMed:11435484}.

Tissue specificity: Expressed in eosinophils and neutrophils, not expressed in peripheral monocytes or lymphocytes. {ECO:0000269|PubMed:11435484}.

Ptm: Autocitrullination at Arg-372 and Arg-374 inactivates the enzyme. {ECO:0000269|PubMed:20201080}.

Disease: Rheumatoid arthritis (RA) [MIM:180300]: An 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. {ECO:0000269|PubMed:12833157}. Note=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). {ECO:0000269|PubMed:12833157, ECO:0000269|PubMed:21245532}.

Similarity: Belongs to the protein arginine deiminase family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		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 (PubMed:15339660, PubMed:15345777, PubMed:16567635, PubMed:21245532). 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) (PubMed:15339660, PubMed:15345777, PubMed:16567635, PubMed:21245532). 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 (PubMed:15339660, PubMed:15345777, PubMed:16567635, PubMed:21245532). Promotes profound chromatin decondensation during the innate immune response to infection in neutrophils by mediating formation of H1R54ci (PubMed:18209087). Required for the formation of neutrophil extracellular traps (NETs); NETs are mainly composed of DNA fibers and are released by neutrophils to bind pathogens during inflammation (By similarity). Citrullination of histone H3 prevents their methylation by CARM1 and HRMT1L2/PRMT1 and represses transcription (PubMed:15345777). Citrullinates EP300/P300 at 'Arg- 2142', which favors its interaction with NCOA2/GRIP1 (PubMed:15731352). {ECO:0000250\|UniProtKB:Q9Z183, ECO:0000269\|PubMed:15339660, ECO:0000269\|PubMed:15345777, ECO:0000269\|PubMed:15731352, ECO:0000269\|PubMed:16567635, ECO:0000269\|PubMed:18209087, ECO:0000269\|PubMed:21245532}.


Catalytic activity:		Reaction=H2O + L-arginyl-[protein] = L-citrullyl-[protein] + NH4(+); Xref=Rhea:RHEA:18089, Rhea:RHEA-COMP:10532, Rhea:RHEA-COMP:10588, ChEBI:CHEBI:15377, ChEBI:CHEBI:28938, ChEBI:CHEBI:29965, ChEBI:CHEBI:83397; EC=3.5.3.15; Evidence={ECO:0000269\|PubMed:16567635, ECO:0000269\|PubMed:21245532};
Cofactor:		Name=Ca(2+); Xref=ChEBI:CHEBI:29108; Evidence={ECO:0000269\|PubMed:15629448, ECO:0000269\|PubMed:16567635, ECO:0000269\|PubMed:17002273}; Note=Binds 5 Ca(2+) ions per subunit. {ECO:0000269\|PubMed:15629448, ECO:0000269\|PubMed:16567635, ECO:0000269\|PubMed:17002273};
Activity regulation:		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-N(5)-(2-fluoro-1-iminoethyl)-L-ornithine amide (o-F- amidine) and N-alpha-(2-carboxyl)benzoyl-N(5)-(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). {ECO:0000269\|PubMed:17002273, ECO:0000269\|PubMed:21882827, ECO:0000269\|PubMed:22004374}.
Biophysicochemical properties:		Kinetic parameters: KM=0.055 mM for fibrinogen {ECO:0000269\|PubMed:15629448}; KM=0.064 mM for filaggrin {ECO:0000269\|PubMed:15629448}; Vmax=33.2 umol/h/mg enzyme toward fibrinogen {ECO:0000269\|PubMed:15629448}; Vmax=8.0 umol/h/mg enzyme toward filaggrin {ECO:0000269\|PubMed:15629448}; pH dependence: Optimum pH is 6.5-9.0. {ECO:0000269\|PubMed:15629448};
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:15629448}. Nucleus {ECO:0000269\|PubMed:15629448}. Cytoplasmic granule {ECO:0000269\|PubMed:11435484}. Note=Cytoplasmic granules of eosinophils and neutrophils. {ECO:0000269\|PubMed:11435484}.
Tissue specificity:		Expressed in eosinophils and neutrophils, not expressed in peripheral monocytes or lymphocytes. {ECO:0000269\|PubMed:11435484}.
Ptm:		Autocitrullination at Arg-372 and Arg-374 inactivates the enzyme. {ECO:0000269\|PubMed:20201080}.
Disease:		Rheumatoid arthritis (RA) [MIM:180300]: An 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. {ECO:0000269\|PubMed:12833157}. Note=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). {ECO:0000269\|PubMed:12833157, ECO:0000269\|PubMed:21245532}.
Similarity:		Belongs to the protein arginine deiminase family. {ECO:0000305}.