NameProtein-arginine deiminase type-4
Synonyms
  • 3.5.3.15
  • HL-60 PAD
  • PAD4
  • PADI5
  • PDI5
  • Peptidylarginine deiminase IV
  • Protein-arginine deiminase type IV
Gene NamePADI4
OrganismHuman
Amino acid sequence
>lcl|BSEQ0016309|Protein-arginine deiminase type-4
MAQGTLIRVTPEQPTHAVCVLGTLTQLDICSSAPEDCTSFSINASPGVVVDIAHGPPAKK
KSTGSSTWPLDPGVEVTLTMKVASGSTGDQKVQISYYGPKTPPVKALLYLTGVEISLCAD
ITRTGKVKPTRAVKDQRTWTWGPCGQGAILLVNCDRDNLESSAMDCEDDEVLDSEDLQDM
SLMTLSTKTPKDFFTNHTLVLHVARSEMDKVRVFQATRGKLSSKCSVVLGPKWPSHYLMV
PGGKHNMDFYVEALAFPDTDFPGLITLTISLLDTSNLELPEAVVFQDSVVFRVAPWIMTP
NTQPPQEVYACSIFENEDFLKSVTTLAMKAKCKLTICPEEENMDDQWMQDEMEIGYIQAP
HKTLPVVFDSPRNRGLKEFPIKRVMGPDFGYVTRGPQTGGISGLDSFGNLEVSPPVTVRG
KEYPLGRILFGDSCYPSNDSRQMHQALQDFLSAQQVQAPVKLYSDWLSVGHVDEFLSFVP
APDRKGFRLLLASPRSCYKLFQEQQNEGHGEALLFEGIKKKKQQKIKNILSNKTLREHNS
FVERCIDWNRELLKRELGLAESDIIDIPQLFKLKEFSKAEAFFPNMVNMLVLGKHLGIPK
PFGPVINGRCCLEEKVCSLLEPLGLQCTFINDFFTYHIRHGEVHCGTNVRRKPFSFKWWN
MVP
Number of residues663
Molecular Weight74078.65
Theoretical pI6.56
GO Classification
Functions
  • calcium ion binding
  • protein-arginine deiminase activity
  • arginine deiminase activity
Processes
  • stem cell population maintenance
  • chromatin modification
  • chromatin organization
  • protein citrullination
  • chromatin remodeling
  • nucleosome assembly
  • histone citrullination
  • histone H3-R26 citrullination
  • cellular protein modification process
  • innate immune response
  • regulation of transcription, DNA-templated
  • transcription, DNA-templated
Components
  • cytoplasm
  • nucleus
  • nucleoplasm
General FunctionProtein-arginine deiminase activity
Specific FunctionCatalyzes 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.
Pfam Domain Function
Transmembrane RegionsNot Available
GenBank Protein ID5913971
UniProtKB IDQ9UM07
UniProtKB Entry NamePADI4_HUMAN
Cellular LocationCytoplasm
Gene sequence
>lcl|BSEQ0016310|Protein-arginine deiminase type-4 (PADI4)
ATGGCCCAGGGGACATTGATCCGTGTGACCCCAGAGCAGCCCACCCATGCCGTGTGTGTG
CTGGGCACCTTGACTCAGCTTGACATCTGCAGCTCTGCCCCTGAGGACTGCACGTCCTTC
AGCATCAACGCCTCCCCAGGGGTGGTCGTGGATATTGCCCACGGCCCTCCAGCCAAGAAG
AAATCCACAGGTTCCTCCACATGGCCCCTGGACCCTGGGGTAGAGGTGACCCTGACGATG
AAAGTGGCCAGTGGTAGCACAGGCGACCAGAAGGTTCAGATTTCATACTACGGACCCAAG
ACTCCACCAGTCAAAGCTCTACTCTACCTCACCGGGGTGGAAATCTCCTTGTGCGCAGAC
ATCACCCGCACCGGCAAAGTGAAGCCAACCAGAGCTGTGAAAGATCAGAGGACCTGGACC
TGGGGCCCTTGTGGACAGGGTGCCATCCTGCTGGTGAACTGTGACAGAGACAATCTCGAA
TCTTCTGCCATGGACTGCGAGGATGATGAAGTGCTTGACAGCGAAGACCTGCAGGACATG
TCGCTGATGACCCTGAGCACGAAGACCCCCAAGGACTTCTTCACAAACCATACACTGGTG
CTCCACGTGGCCAGGTCTGAGATGGACAAAGTGAGGGTGTTTCAGGCCACACGGGGCAAA
CTGTCCTCCAAGTGCAGCGTAGTCTTGGGTCCCAAGTGGCCCTCTCACTACCTGATGGTC
CCCGGTGGAAAGCACAACATGGACTTCTACGTGGAGGCCCTCGCTTTCCCGGACACCGAC
TTCCCGGGGCTCATTACCCTCACCATCTCCCTGCTGGACACGTCCAACCTGGAGCTCCCC
GAGGCTGTGGTGTTCCAAGACAGCGTGGTCTTCCGCGTGGCGCCCTGGATCATGACCCCC
AACACCCAGCCCCCGCAGGAGGTGTACGCGTGCAGTATTTTTGAAAATGAGGACTTCCTG
AAGTCAGTGACTACTCTGGCCATGAAAGCCAAGTGCAAGCTGACCATCTGCCCTGAGGAG
GAGAACATGGATGACCAGTGGATGCAGGATGAAATGGAGATCGGCTACATCCAAGCCCCA
CACAAAACGCTGCCCGTGGTCTTCGACTCTCCAAGGAACAGAGGCCTGAAGGAGTTTCCC
ATCAAACGCGTGATGGGTCCAGATTTTGGCTATGTAACTCGAGGGCCCCAAACAGGGGGT
ATCAGTGGACTGGACTCCTTTGGGAACCTGGAAGTGAGCCCCCCAGTCACAGTCAGGGGC
AAGGAATACCCGCTGGGCAGGATTCTCTTCGGGGACAGCTGTTATCCCAGCAATGACAGC
CGGCAGATGCACCAGGCCCTGCAGGACTTCCTCAGTGCCCAGCAGGTGCAGGCCCCTGTG
AAGCTCTATTCTGACTGGCTGTCCGTGGGCCACGTGGACGAGTTCCTGAGCTTTGTGCCA
GCACCCGACAGGAAGGGCTTCCGGCTGCTCCTGGCCAGCCCCAGGTCCTGCTACAAACTG
TTCCAGGAGCAGCAGAATGAGGGCCACGGGGAGGCCCTGCTGTTCGAAGGGATCAAGAAA
AAAAAACAGCAGAAAATAAAGAACATTCTGTCAAACAAGACATTGAGAGAACATAATTCA
TTTGTGGAGAGATGCATCGACTGGAACCGCGAGCTGCTGAAGCGGGAGCTGGGCCTGGCC
GAGAGTGACATCATTGACATCCCGCAGCTCTTCAAGCTCAAAGAGTTCTCTAAGGCGGAA
GCTTTTTTCCCCAACATGGTGAACATGCTGGTGCTAGGGAAGCACCTGGGCATCCCCAAG
CCCTTCGGGCCCGTCATCAACGGCCGCTGCTGCCTGGAGGAGAAGGTGTGTTCCCTGCTG
GAGCCACTGGGCCTCCAGTGCACCTTCATCAACGACTTCTTCACCTACCACATCAGGCAT
GGGGAGGTGCACTGCGGCACCAACGTGCGCAGAAAGCCCTTCTCCTTCAAGTGGTGGAAC
ATGGTGCCCTGA
GenBank Gene IDAB017919
GeneCard IDNot Available
GenAtlas IDPADI4
HGNC IDHGNC:18368
Chromosome Location1
Locus1p36.13
References
  1. Nakashima K, Hagiwara T, Ishigami A, Nagata S, Asaga H, Kuramoto M, Senshu T, Yamada M: Molecular characterization of peptidylarginine deiminase in HL-60 cells induced by retinoic acid and 1alpha,25-dihydroxyvitamin D(3). J Biol Chem. 1999 Sep 24;274(39):27786-92. 10488123
  2. Chavanas S, Mechin MC, Takahara H, Kawada A, Nachat R, Serre G, Simon M: Comparative analysis of the mouse and human peptidylarginine deiminase gene clusters reveals highly conserved non-coding segments and a new human gene, PADI6. Gene. 2004 Apr 14;330:19-27. 15087120
  3. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. 14702039
  4. Gregory SG, Barlow KF, McLay KE, Kaul R, Swarbreck D, Dunham A, Scott CE, Howe KL, Woodfine K, Spencer CC, Jones MC, Gillson C, Searle S, Zhou Y, Kokocinski F, McDonald L, Evans R, Phillips K, Atkinson A, Cooper R, Jones C, Hall RE, Andrews TD, Lloyd C, Ainscough R, Almeida JP, Ambrose KD, Anderson F, Andrew RW, Ashwell RI, Aubin K, Babbage AK, Bagguley CL, Bailey J, Beasley H, Bethel G, Bird CP, Bray-Allen S, Brown JY, Brown AJ, Buckley D, Burton J, Bye J, Carder C, Chapman JC, Clark SY, Clarke G, Clee C, Cobley V, Collier RE, Corby N, Coville GJ, Davies J, Deadman R, Dunn M, Earthrowl M, Ellington AG, Errington H, Frankish A, Frankland J, French L, Garner P, Garnett J, Gay L, Ghori MR, Gibson R, Gilby LM, Gillett W, Glithero RJ, Grafham DV, Griffiths C, Griffiths-Jones S, Grocock R, Hammond S, Harrison ES, Hart E, Haugen E, Heath PD, Holmes S, Holt K, Howden PJ, Hunt AR, Hunt SE, Hunter G, Isherwood J, James R, Johnson C, Johnson D, Joy A, Kay M, Kershaw JK, Kibukawa M, Kimberley AM, King A, Knights AJ, Lad H, Laird G, Lawlor S, Leongamornlert DA, Lloyd DM, Loveland J, Lovell J, Lush MJ, Lyne R, Martin S, Mashreghi-Mohammadi M, Matthews L, Matthews NS, McLaren S, Milne S, Mistry S, Moore MJ, Nickerson T, O'Dell CN, Oliver K, Palmeiri A, Palmer SA, Parker A, Patel D, Pearce AV, Peck AI, Pelan S, Phelps K, Phillimore BJ, Plumb R, Rajan J, Raymond C, Rouse G, Saenphimmachak C, Sehra HK, Sheridan E, Shownkeen R, Sims S, Skuce CD, Smith M, Steward C, Subramanian S, Sycamore N, Tracey A, Tromans A, Van Helmond Z, Wall M, Wallis JM, White S, Whitehead SL, Wilkinson JE, Willey DL, Williams H, Wilming L, Wray PW, Wu Z, Coulson A, Vaudin M, Sulston JE, Durbin R, Hubbard T, Wooster R, Dunham I, Carter NP, McVean G, Ross MT, Harrow J, Olson MV, Beck S, Rogers J, Bentley DR, Banerjee R, Bryant SP, Burford DC, Burrill WD, Clegg SM, Dhami P, Dovey O, Faulkner LM, Gribble SM, Langford CF, Pandian RD, Porter KM, Prigmore E: The DNA sequence and biological annotation of human chromosome 1. Nature. 2006 May 18;441(7091):315-21. 16710414
  5. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. 15489334
  6. Asaga H, Nakashima K, Senshu T, Ishigami A, Yamada M: Immunocytochemical localization of peptidylarginine deiminase in human eosinophils and neutrophils. J Leukoc Biol. 2001 Jul;70(1):46-51. 11435484
  7. Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, Nagasaki M, Nakayama-Hamada M, Kawaida R, Ono M, Ohtsuki M, Furukawa H, Yoshino S, Yukioka M, Tohma S, Matsubara T, Wakitani S, Teshima R, Nishioka Y, Sekine A, Iida A, Takahashi A, Tsunoda T, Nakamura Y, Yamamoto K: Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet. 2003 Aug;34(4):395-402. 12833157
  8. Cuthbert GL, Daujat S, Snowden AW, Erdjument-Bromage H, Hagiwara T, Yamada M, Schneider R, Gregory PD, Tempst P, Bannister AJ, Kouzarides T: Histone deimination antagonizes arginine methylation. Cell. 2004 Sep 3;118(5):545-53. 15339660
  9. Wang Y, Wysocka J, Sayegh J, Lee YH, Perlin JR, Leonelli L, Sonbuchner LS, McDonald CH, Cook RG, Dou Y, Roeder RG, Clarke S, Stallcup MR, Allis CD, Coonrod SA: Human PAD4 regulates histone arginine methylation levels via demethylimination. Science. 2004 Oct 8;306(5694):279-83. Epub 2004 Sep 2. 15345777
  10. Nakayama-Hamada M, Suzuki A, Kubota K, Takazawa T, Ohsaka M, Kawaida R, Ono M, Kasuya A, Furukawa H, Yamada R, Yamamoto K: Comparison of enzymatic properties between hPADI2 and hPADI4. Biochem Biophys Res Commun. 2005 Feb 4;327(1):192-200. 15629448
  11. Lee YH, Coonrod SA, Kraus WL, Jelinek MA, Stallcup MR: Regulation of coactivator complex assembly and function by protein arginine methylation and demethylimination. Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3611-6. Epub 2005 Feb 24. 15731352
  12. Neeli I, Khan SN, Radic M: Histone deimination as a response to inflammatory stimuli in neutrophils. J Immunol. 2008 Feb 1;180(3):1895-902. 18209087
  13. Andrade F, Darrah E, Gucek M, Cole RN, Rosen A, Zhu X: Autocitrullination of human peptidyl arginine deiminase type 4 regulates protein citrullination during cell activation. Arthritis Rheum. 2010 Jun;62(6):1630-40. doi: 10.1002/art.27439. 20201080
  14. Arita K, Hashimoto H, Shimizu T, Nakashima K, Yamada M, Sato M: Structural basis for Ca(2+)-induced activation of human PAD4. Nat Struct Mol Biol. 2004 Aug;11(8):777-83. Epub 2004 Jul 11. 15247907
  15. Arita K, Shimizu T, Hashimoto H, Hidaka Y, Yamada M, Sato M: Structural basis for histone N-terminal recognition by human peptidylarginine deiminase 4. Proc Natl Acad Sci U S A. 2006 Apr 4;103(14):5291-6. Epub 2006 Mar 27. 16567635
  16. Luo Y, Arita K, Bhatia M, Knuckley B, Lee YH, Stallcup MR, Sato M, Thompson PR: Inhibitors and inactivators of protein arginine deiminase 4: functional and structural characterization. Biochemistry. 2006 Oct 3;45(39):11727-36. 17002273
  17. Horikoshi N, Tachiwana H, Saito K, Osakabe A, Sato M, Yamada M, Akashi S, Nishimura Y, Kagawa W, Kurumizaka H: Structural and biochemical analyses of the human PAD4 variant encoded by a functional haplotype gene. Acta Crystallogr D Biol Crystallogr. 2011 Feb;67(Pt 2):112-8. doi: 10.1107/S0907444910051711. Epub 2011 Jan 8. 21245532
  18. Causey CP, Jones JE, Slack JL, Kamei D, Jones LE, Subramanian V, Knuckley B, Ebrahimi P, Chumanevich AA, Luo Y, Hashimoto H, Sato M, Hofseth LJ, Thompson PR: The development of 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) as second generation protein arginine deiminase (PAD) inhibitors. J Med Chem. 2011 Oct 13;54(19):6919-35. doi: 10.1021/jm2008985. Epub 2011 Sep 16. 21882827
  19. Jones JE, Slack JL, Fang P, Zhang X, Subramanian V, Causey CP, Coonrod SA, Guo M, Thompson PR: Synthesis and screening of a haloacetamidine containing library to identify PAD4 selective inhibitors. ACS Chem Biol. 2012 Jan 20;7(1):160-5. doi: 10.1021/cb200258q. Epub 2011 Oct 21. 22004374
  20. Hoppe B, Heymann GA, Tolou F, Kiesewetter H, Doerner T, Salama A: High variability of peptidylarginine deiminase 4 (PADI4) in a healthy white population: characterization of six new variants of PADI4 exons 2-4 by a novel haplotype-specific sequencing-based approach. J Mol Med (Berl). 2004 Nov;82(11):762-7. Epub 2004 Aug 25. 15338034