2KYU

The solution structure of the PHD3 finger of MLL

2KYU の概要

• エントリーDOI: 10.2210/pdb2kyu/pdb
• NMR情報: BMRB: 16983
• 分子名称: Histone-lysine N-methyltransferase MLL, ZINC ION (2 entities in total)
• 機能のキーワード: phd, chromatin regulation, transcription, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 7850.45

構造登録者

Park, S.,Bushweller, J.H. (登録日: 2010-06-08, 公開日: 2010-08-25, 最終更新日: 2024-05-01)

主引用文献

Park, S.,Osmers, U.,Raman, G.,Schwantes, R.H.,Diaz, M.O.,Bushweller, J.H.
The PHD3 domain of MLL acts as a CYP33-regulated switch between MLL-mediated activation and repression.
Biochemistry, 49:6576-6586, 2010

PubMed Abstract: The mixed lineage leukemia (MLL) gene plays a critical role in epigenetic regulation of gene expression and is a frequent target of chromosomal translocations leading to leukemia. MLL plant homeodomain 3 (PHD3) is lost in all MLL translocation products, and reinsertion of PHD3 into MLL fusion proteins abrogates their transforming activity. PHD3 has been shown to interact with the RNA-recognition motif (RRM) domain of human nuclear Cyclophilin33 (CYP33). Here, we show that CYP33 mediates downregulation of the expression of MLL target genes HOXC8, HOXA9, CDKN1B, and C-MYC, in a proline isomerase-dependent manner. This downregulation correlates with the reduction of trimethylated lysine 4 of histone H3 (H3K4me3) and histone H3 acetylation. We have structurally characterized both the PHD3 and CYP33 RRM domains and analyzed their binding to one another. The PHD3 domain binds H3K4me3 (preferentially) and the CYP33 RRM domain at distinct sites. Our binding data show that binding of H3K4me3 to PHD3 and binding of the CYP33 RRM domain to PHD3 are mutually inhibitory, implying that PHD3 is a molecular switch for the transition between activation and repression of target genes. To explore the possible mechanism of CYP33/PHD3-mediated repression, we have analyzed the CYP33 proline isomerase activity on various H3 and H4 peptides and shown selectivity for two sites in H3. Our results provide a possible mechanism for the MLL PHD3 domain to act as a switch between activation and repression.

PubMed: 20677832
DOI: 10.1021/bi1009387

実験手法

SOLUTION NMR