Molecular basis for chromatin binding and regulation of MLL5
Molecular basis for chromatin binding and regulation of MLL5
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DOI：
10.1073/pnas.1310156110
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发表时间：
2013-07-09
影响因子：
11.1
通讯作者：
Kutateladze, Tatiana G.
中科院分区：
文献类型：
--
作者：
Ali, Muzaffar;Rincon-Arano, Hector;Kutateladze, Tatiana G.
人类混合谱系白血病5（MLL 5）蛋白介导造血细胞稳态，细胞周期和生存;然而，MLL 5活动的分子基础仍然未知。在这里，我们发现MLL 5通过其植物同源结构域指与组蛋白标记H3 K4 me 3的相互作用被招募到基因丰富的常染色质区。MLL 5植物同源结构域与H3 K4 me 3肽复合的1.48埃分辨率晶体结构揭示了非经典结合机制，其中K4 me 3通过单个芳香族残基和天冬氨酸被识别。结合诱导由C-末端α-螺旋介导的独特的His-Asp交换重排。H3 T3和H3 T6的磷酸化在体外和体内消除与H3 K4 me 3的结合，在有丝分裂中从染色质释放MLL 5。这种调节开关在果蝇的MLL 5直系同源物UpSET中是保守的，并表明了H3 K4 me 3靶向的发育控制。总之，我们的研究结果提供了第一个深入了解的分子基础上的招聘，排斥和调节MLL 5在染色质。
The human mixed-lineage leukemia 5 (MLL5) protein mediates hematopoietic cell homeostasis, cell cycle, and survival; however, the molecular basis underlying MLL5 activities remains unknown. Here, we show that MLL5 is recruited to gene-rich euchromatic regions via the interaction of its plant homeodomain finger with the histone mark H3K4me3. The 1.48-angstrom resolution crystal structure of MLL5 plant homeodomain in complex with the H3K4me3 peptide reveals a noncanonical binding mechanism, whereby K4me3 is recognized through a single aromatic residue and an aspartate. The binding induces a unique His-Asp swapping rearrangement mediated by a C-terminal alpha-helix. Phosphorylation of H3T3 and H3T6 abrogates the association with H3K4me3 in vitro and in vivo, releasing MLL5 from chromatin in mitosis. This regulatory switch is conserved in the Drosophila ortholog of MLL5, UpSET, and suggests the developmental control for targeting of H3K4me3. Together, our findings provide first insights into the molecular basis for the recruitment, exclusion, and regulation of MLL5 at chromatin.