Modification of histones by peptidylarginine deiminase and its biological significance

• Project/Area Number: 15570122
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Yokohama City University
• Principal Investigator: YAMADA Michiyuki Yokohama City University, Graduate School of Integrated Science, Professor, 総合理学研究科, 教授 (10076995)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,300,000 (Direct Cost: ¥3,300,000); Fiscal Year 2004: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
• Keywords: deimination / Posttranslational modification / peptidylarginine deiminase / histone / Citrullination / neutrophil / eosinophil / monocytes

Research Abstract

Peptidylarginine deiminase (PADI) 4 deiminates preferentially core histones in HL-60 granulocytes and bloodstream granulocytes stimulated with calcium ionophore. In this study we determined the deimination sites of histones. Deiminated histone H4 and H2A were isolated and digested with proteases. Their degests were separated by RP-HPLC. Deiminated peptides were identified by mass spectrometry. The deimination occurred at R3 of the N-terminal sequence Ac-SGRGK common to H2A and H4. This indicates that the target site in vivo for PADI4 is very restricted.
As for a role of PADI4, we found that PADI4 can act as a repressor for transcriptional activation of pS2 promoter by estrogen. PADI4 antagonizes dimethylation of histone H3 R17 which is required for transcription of the promoter by deiminating monomethyl arginine and arginine into citrulline.
Crystal structures of Ca^<2+> free PADI4 and Ca^<2+> bound PADI4 mutants with and without substrate revealed that Ca^<2+> binding induces conformational changes that generates the active site cleft.

Research Products

• [Journal Article] Structual basis for Ca^<2+>-induced activation of human PAD4 (2004)
  • Author(s): Arita K, Hashimoto H, Shimizu T, Nakashima K, Yamada M, Sato M
  • Journal Title: Nature SMB 11 Pages: 777-783
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Histone Deimination Antagonizes Arginine methylation (2004)
  • Author(s): Cuthbert GL, Daujat S, Snowden AW, Erdjument-Bromage H, Hagiwara T, Yamada M, Schneider R, Gregory PD, Tempst P, Bannister AJ, Kouzarides T
  • Journal Title: Cell 118 Pages: 545-553
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Structual basis for Ca^<2+>-induced activation of human PAD4 (2004)
  • Author(s): Arita, K., Hashimoto, H., Shimizu, T., Nakashima, K., Yamada, M., Sato, M.
  • Journal Title: Nature SMB 11 Pages: 777-783
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Histone Deimination Antagonizes Arginine methylation (2004)
  • Author(s): Cuthbert, G.L., Daujat, S., Snowden, A.W., Erdjument-Bromage, H., Hagiwara, T., Yamada, M,.Schneider, R., Gregory, P.D., Tempst, P., Bannister, A.J., Kouzarides, T.
  • Journal Title: Cell 118 Pages: 545-553
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Histone Deimination Antagonizes Arginine methylation (2004)
  • Author(s): Cuthbert GL, Daujat S, Snowden AW, Erdjument-Bromage H, Hagiwara T, Yanada M, Schneider R, Gregory PD, Tempst P, Bannister AJ, Kouzarides T
  • Journal Title: Cell 118 Pages: 545-553
• [Journal Article] Crystallization and preliminary X-ray crystallographic analysis of human peptidylarginine deiminase V (2003)
  • Author(s): Arita K, Hashimoto H, Shimizu T, Yamada M, Sato M
  • Journal Title: Acta Cryst.D 59 Pages: 2332-2333
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Crystallization and preliminary X-ray crystallographic analysis of human peptidylarginine deiminase V (2003)
  • Author(s): Arita, K., Hashimoto, H., Shimizu, T., Yamada, M., Sato, M.
  • Journal Title: Acta Cryst. D 59 Pages: 2332-2333
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Deimination of Histone H2A and H4 at arginine 3 in HL-60 granulocutes
  • Author(s): Hagiwara T, Hidaka Y, Yamada M
  • Journal Title: Biochemistry (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Deimination of Histone H2A and H4 at arginine 3 in HL-60 granulocutes
  • Author(s): Hagiwara, T., Hidaka, Y., Yamada, M.
  • Journal Title: Biochemistry (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Deimination of Histone H2A and H4 at arginine 3 in HL-60 granulocutes
  • Author(s): Hagiwara T, Hidaka Y, Yamada M
  • Journal Title: Biochemistry (in press)
• [Publications] Arita, K., et al.: "Crystallization and preliminarv X ray crvstallographic analysis of human peptidylarginine deiminase V"Acta Cryst.D.. 59. 2332-2333 (2003)