4U7P

Crystal structure of DNMT3A-DNMT3L complex

4U7P の概要

• エントリーDOI: 10.2210/pdb4u7p/pdb
• 関連するPDBエントリー: 4U7T
• 分子名称: DNA (cytosine-5)-methyltransferase 3A, DNA (cytosine-5)-methyltransferase 3-like, ZINC ION, ... (4 entities in total)
• 機能のキーワード: dna methyltransferase, autoinhibitory form, transferase-transferase regulator complex, transferase/transferase regulator
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Nucleus : Q9Y6K1 Q9UJW3
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 78050.64

構造登録者

Wang, L.,Guo, X.,Li, J.,Xiao, J.,Yin, X.,He, S.,Wang, J.,Xu, Y. (登録日: 2014-07-31, 公開日: 2014-11-12, 最終更新日: 2023-11-08)

主引用文献

Guo, X.,Wang, L.,Li, J.,Ding, Z.,Xiao, J.,Yin, X.,He, S.,Shi, P.,Dong, L.,Li, G.,Tian, C.,Wang, J.,Cong, Y.,Xu, Y.
Structural insight into autoinhibition and histone H3-induced activation of DNMT3A
Nature, 517:640-644, 2015

PubMed Abstract: DNA methylation is an important epigenetic modification that is essential for various developmental processes through regulating gene expression, genomic imprinting, and epigenetic inheritance. Mammalian genomic DNA methylation is established during embryogenesis by de novo DNA methyltransferases, DNMT3A and DNMT3B, and the methylation patterns vary with developmental stages and cell types. DNA methyltransferase 3-like protein (DNMT3L) is a catalytically inactive paralogue of DNMT3 enzymes, which stimulates the enzymatic activity of Dnmt3a. Recent studies have established a connection between DNA methylation and histone modifications, and revealed a histone-guided mechanism for the establishment of DNA methylation. The ATRX-DNMT3-DNMT3L (ADD) domain of Dnmt3a recognizes unmethylated histone H3 (H3K4me0). The histone H3 tail stimulates the enzymatic activity of Dnmt3a in vitro, whereas the molecular mechanism remains elusive. Here we show that DNMT3A exists in an autoinhibitory form and that the histone H3 tail stimulates its activity in a DNMT3L-independent manner. We determine the crystal structures of DNMT3A-DNMT3L (autoinhibitory form) and DNMT3A-DNMT3L-H3 (active form) complexes at 3.82 and 2.90 Å resolution, respectively. Structural and biochemical analyses indicate that the ADD domain of DNMT3A interacts with and inhibits enzymatic activity of the catalytic domain (CD) through blocking its DNA-binding affinity. Histone H3 (but not H3K4me3) disrupts ADD-CD interaction, induces a large movement of the ADD domain, and thus releases the autoinhibition of DNMT3A. The finding adds another layer of regulation of DNA methylation to ensure that the enzyme is mainly activated at proper targeting loci when unmethylated H3K4 is present, and strongly supports a negative correlation between H3K4me3 and DNA methylation across the mammalian genome. Our study provides a new insight into an unexpected autoinhibition and histone H3-induced activation of the de novo DNA methyltransferase after its initial genomic positioning.

PubMed: 25383530
DOI: 10.1038/nature13899

実験手法

X-RAY DIFFRACTION (3.821 Å)