9GBF

X-RAY structure of PHDvC5HCH tandem domain of NSD2

9GBF の概要

• エントリーDOI: 10.2210/pdb9gbf/pdb
• 分子名称: Histone-lysine N-methyltransferase NSD2, ZINC ION, SODIUM ION, ... (6 entities in total)
• 機能のキーワード: histone lysine methyl transferase, nuclear receptor binding set domain, myeloma, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 23797.55

構造登録者

Musco, G.,Cocomazzi, P.,Berardi, A.,Knapp, S.,Kramer, A. (登録日: 2024-07-31, 公開日: 2024-12-18, 最終更新日: 2025-01-22)

主引用文献

Berardi, A.,Kaestner, C.L.,Ghitti, M.,Quilici, G.,Cocomazzi, P.,Li, J.,Ballabio, F.,Zucchelli, C.,Knapp, S.,Licht, J.D.,Musco, G.
The C-terminal PHDVC5HCH tandem domain of NSD2 is a combinatorial reader of unmodified H3K4 and tri-methylated H3K27 that regulates transcription of cell adhesion genes in multiple myeloma.
Nucleic Acids Res., 53:-, 2025

PubMed Abstract: Histone methyltransferase NSD2 (MMSET) overexpression in multiple myeloma (MM) patients plays an important role in the development of this disease subtype. Through the expansion of transcriptional activating H3K36me2 and the suppression of repressive H3K27me3 marks, NSD2 activates an aberrant set of genes that contribute to myeloma growth, adhesive and invasive activities. NSD2 transcriptional activity also depends on its non-catalytic domains, which facilitate its recruitment to chromatin through histone binding. In this study, using NMR, ITC and molecular dynamics simulations, we show that the tandem PHD domain of NSD2 (PHDVC5HCHNSD2) is a combinatorial reader of unmodified histone H3K4 and tri-methylated H3K27 (H3K27me3). This is the first PHD tandem cassette known to decode the methylation status of H3K27. Importantly, in a NSD2-dependent MM cellular model, we show that expression of NSD2 mutants, engineered to disrupt the interaction between H3K27me3 and PHDVC5HCH, display in comparison to wild-type NSD2: incomplete loss of H3K27 methylation throughout the genome, decreased activation of adhesive properties and cell adhesion genes, and a decrease of the corresponding H3K27ac signal at promoters. Collectively, these data suggest that the PHDVC5HCH domain of NSD2 plays an important role in modulating gene expression and chromatin modification, providing new opportunities for pharmacological intervention.

PubMed: 39656918
DOI: 10.1093/nar/gkae1121

実験手法

X-RAY DIFFRACTION (1.76 Å)