7U5V

Crystal structure of the Mixed Lineage Leukaemia (MLL1) SET Domain with the cofactor product S-Adenosylhomocysteine and Borealin peptide

7U5V の概要

• エントリーDOI: 10.2210/pdb7u5v/pdb
• 分子名称: Histone-lysine N-methyltransferase 2A, Borealin, ZINC ION, ... (4 entities in total)
• 機能のキーワード: mll1-set, borealin, histone methyltransferase, non-histone substrate, gene regulation
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 19542.93

構造登録者

An, S.,Cho, U.S.,Oh, H.,Sha, L.,Xu, J.,Kim, S.,Yang, W.,An, W.,Dou, Y. (登録日: 2022-03-02, 公開日: 2023-09-27, 最終更新日: 2024-04-10)

主引用文献

Sha, L.,Yang, Z.,An, S.,Yang, W.,Kim, S.,Oh, H.,Xu, J.,Yin, J.,Wang, H.,Lenz, H.J.,An, W.,Cho, U.S.,Dou, Y.
Non-canonical MLL1 activity regulates centromeric phase separation and genome stability.
Nat.Cell Biol., 25:1637-1649, 2023

PubMed Abstract: Epigenetic dysregulation is a prominent feature in cancer, as exemplified by frequent mutations in chromatin regulators, including the MLL/KMT2 family of histone methyltransferases. Although MLL1/KMT2A activity on H3K4 methylation is well documented, their non-canonical activities remain mostly unexplored. Here we show that MLL1/KMT2A methylates Borealin K143 in the intrinsically disordered region essential for liquid-liquid phase separation of the chromosome passenger complex (CPC). The co-crystal structure highlights the distinct binding mode of the MLL1 SET domain with Borealin K143. Inhibiting MLL1 activity or mutating Borealin K143 to arginine perturbs CPC phase separation, reduces Aurora kinase B activity, and impairs the resolution of erroneous kinetochore-microtubule attachments and sister-chromatid cohesion. They significantly increase chromosome instability and aneuploidy in a subset of hepatocellular carcinoma, resulting in growth inhibition. These results demonstrate a non-redundant function of MLL1 in regulating inner centromere liquid condensates and genome stability via a non-canonical enzymatic activity.

PubMed: 37945831
DOI: 10.1038/s41556-023-01270-1

実験手法

X-RAY DIFFRACTION (2.59 Å)