PADI4 explained

Protein-arginine deiminase type-4, is a human protein which in humans is encoded by the PADI4 gene.^{[1] [2]} The protein as an enzyme, specifically protein-arginine deiminase, a type of hydrolase.

Molecular biology

The human gene is found on the short arm of Chromosome 1 near the telomere (1p36.13). It is located on the Watson (plus) strand and is 55,806 bases long. The protein is 663 amino acids long with a molecular weight of 74,095 Da.^[1]

Function

This gene is a member of a gene family which encodes enzymes responsible for the conversion of arginine to citrulline residues (citrullination). This gene may play a role in granulocyte and macrophage development leading to inflammation and immune response.^[2] PADI4 plays a role in the epigenetics,^[3] the deimination of arginines on histones H3 and H4 can act antagonistically to arginine methylation.^[4]

The protein may be found in oligomers and binds 5 calcium ions per subunit. It catalyses the reaction:

• Protein L-arginine + H₂O = protein L-citrulline + NH₄⁺

Subcellular and tissue distribution

It is normally found in the cytoplasm, nucleus and in cytoplasmic granules of eosinophils and neutrophils. It is not expressed in peripheral monocytes or lymphocytes. It is also expressed in rheumatoid arthritis synovial tissues.

Further reading

• Nakashima K, Hagiwara T, Ishigami A, Nagata S, Asaga H, Kuramoto M, Senshu T, Yamada M . 6 . Molecular characterization of peptidylarginine deiminase in HL-60 cells induced by retinoic acid and 1alpha,25-dihydroxyvitamin D(3) . The Journal of Biological Chemistry . 274 . 39 . 27786–27792 . September 1999 . 10488123 . 10.1074/jbc.274.39.27786 . free .
• Zhang QH, Ye M, Wu XY, Ren SX, Zhao M, Zhao CJ, Fu G, Shen Y, Fan HY, Lu G, Zhong M, Xu XR, Han ZG, Zhang JW, Tao J, Huang QH, Zhou J, Hu GX, Gu J, Chen SJ, Chen Z . 6 . Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells . Genome Research . 10 . 10 . 1546–1560 . October 2000 . 11042152 . 310934 . 10.1101/gr.140200 .
• Asaga H, Nakashima K, Senshu T, Ishigami A, Yamada M . Immunocytochemical localization of peptidylarginine deiminase in human eosinophils and neutrophils . Journal of Leukocyte Biology . 70 . 1 . 46–51 . July 2001 . 11435484 . 10.1189/jlb.70.1.46 . 11448270 .
• Nakashima K, Hagiwara T, Yamada M . Nuclear localization of peptidylarginine deiminase V and histone deimination in granulocytes . The Journal of Biological Chemistry . 277 . 51 . 49562–49568 . December 2002 . 12393868 . 10.1074/jbc.M208795200 . free .
• 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 . 6 . Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis . Nature Genetics . 34 . 4 . 395–402 . August 2003 . 12833157 . 10.1038/ng1206 . 20136298 .
• Barton A, Bowes J, Eyre S, Spreckley K, Hinks A, John S, Worthington J . A functional haplotype of the PADI4 gene associated with rheumatoid arthritis in a Japanese population is not associated in a United Kingdom population . Arthritis and Rheumatism . 50 . 4 . 1117–1121 . April 2004 . 15077293 . 10.1002/art.20169 .
• Chavanas S, Méchin 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 . 330 . 19–27 . April 2004 . 15087120 . 10.1016/j.gene.2003.12.038 .
• Arita K, Hashimoto H, Shimizu T, Nakashima K, Yamada M, Sato M . Structural basis for Ca(2+)-induced activation of human PAD4 . Nature Structural & Molecular Biology . 11 . 8 . 777–783 . August 2004 . 15247907 . 10.1038/nsmb799 . 11947135 .
• 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 . Journal of Molecular Medicine . 82 . 11 . 762–767 . November 2004 . 15338034 . 10.1007/s00109-004-0584-6 . 8356741 .
• Cuthbert GL, Daujat S, Snowden AW, Erdjument-Bromage H, Hagiwara T, Yamada M, Schneider R, Gregory PD, Tempst P, Bannister AJ, Kouzarides T . 6 . Histone deimination antagonizes arginine methylation . Cell . 118 . 5 . 545–553 . September 2004 . 15339660 . 10.1016/j.cell.2004.08.020 . 8948511 . free .
• 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 . 6 . Human PAD4 regulates histone arginine methylation levels via demethylimination . Science . 306 . 5694 . 279–283 . October 2004 . 15345777 . 10.1126/science.1101400 . 2004Sci...306..279W . 1579362 .
• Nakayama-Hamada M, Suzuki A, Kubota K, Takazawa T, Ohsaka M, Kawaida R, Ono M, Kasuya A, Furukawa H, Yamada R, Yamamoto K . 6 . Comparison of enzymatic properties between hPADI2 and hPADI4 . Biochemical and Biophysical Research Communications . 327 . 1 . 192–200 . February 2005 . 15629448 . 10.1016/j.bbrc.2004.11.152 .
• Lee YH, Coonrod SA, Kraus WL, Jelinek MA, Stallcup MR . Regulation of coactivator complex assembly and function by protein arginine methylation and demethylimination . Proceedings of the National Academy of Sciences of the United States of America . 102 . 10 . 3611–3616 . March 2005 . 15731352 . 553305 . 10.1073/pnas.0407159102 . 2005PNAS..102.3611L . free .
• Kearney PL, Bhatia M, Jones NG, Yuan L, Glascock MC, Catchings KL, Yamada M, Thompson PR . 6 . Kinetic characterization of protein arginine deiminase 4: a transcriptional corepressor implicated in the onset and progression of rheumatoid arthritis . Biochemistry . 44 . 31 . 10570–10582 . August 2005 . 16060666 . 10.1021/bi050292m .
• Ikari K, Kuwahara M, Nakamura T, Momohara S, Hara M, Yamanaka H, Tomatsu T, Kamatani N . 6 . Association between PADI4 and rheumatoid arthritis: a replication study . Arthritis and Rheumatism . 52 . 10 . 3054–3057 . October 2005 . 16200584 . 10.1002/art.21309 .
• Chang X, Han J . Expression of peptidylarginine deiminase type 4 (PAD4) in various tumors . Molecular Carcinogenesis . 45 . 3 . 183–196 . March 2006 . 16355400 . 10.1002/mc.20169 . 40916607 .
• Plenge RM, Padyukov L, Remmers EF, Purcell S, Lee AT, Karlson EW, Wolfe F, Kastner DL, Alfredsson L, Altshuler D, Gregersen PK, Klareskog L, Rioux JD . 6 . Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4 . American Journal of Human Genetics . 77 . 6 . 1044–1060 . December 2005 . 16380915 . 1285162 . 10.1086/498651 .
• Hoppe B, Häupl T, Gruber R, Kiesewetter H, Burmester GR, Salama A, Dörner T . Detailed analysis of the variability of peptidylarginine deiminase type 4 in German patients with rheumatoid arthritis: a case-control study . Arthritis Research & Therapy . 8 . 2 . R34 . 2006 . 16469113 . 1526594 . 10.1186/ar1889 . free .

Notes and References

1. Nakashima K, Hagiwara T, Ishigami A, Nagata S, Asaga H, Kuramoto M, Senshu T, Yamada M . 6 . Molecular characterization of peptidylarginine deiminase in HL-60 cells induced by retinoic acid and 1alpha,25-dihydroxyvitamin D(3) . The Journal of Biological Chemistry . 274 . 39 . 27786–27792 . September 1999 . 10488123 . 10.1074/jbc.274.39.27786 . free .
2. Web site: Entrez Gene: PADI4 peptidyl arginine deiminase, type IV.
3. Sams KL, Mukai C, Marks BA, Mittal C, Demeter EA, Nelissen S, Grenier JK, Tate AE, Ahmed F, Coonrod SA . 6 . Delayed puberty, gonadotropin abnormalities and subfertility in male Padi2/Padi4 double knockout mice . Reproductive Biology and Endocrinology . 20 . 1 . 150 . October 2022 . 36224627 . 10.1186/s12958-022-01018-w . 9555066 . free .
4. Kouzarides T . Chromatin modifications and their function . Cell . 128 . 4 . 693–705 . February 2007 . 17320507 . 10.1016/j.cell.2007.02.005 . free .