Pro isomerization in MLL1 PHD3-bromo cassette connects H3K4me readout to CyP33 and HDAC-mediated repression.
Pro isomerization in MLL1 PHD3-bromo cassette connects H3K4me readout to CyP33 and HDAC-mediated repression.
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DOI：
10.1016/j.cell.2010.05.016
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发表时间：
2010-06-25
期刊：
影响因子：
64.5
通讯作者：
Patel DJ
中科院分区：
文献类型：
--
作者：
Wang Z;Song J;Milne TA;Wang GG;Li H;Allis CD;Patel DJ
MLL 1基因是复发性染色体易位的常见靶标，导致造血前体转化为白血病干细胞。在这里，我们报告的结构-功能的研究，阐明MLL 1结合组蛋白H3 K4 me 3/2标志和亲环素CyP 33的招聘分子事件。CyP 33含有PPIase和RRM结构域，并通过HDAC募集调节MLL 1功能。我们发现CyP 33的PPIase结构域通过PHD 3-Bromo接头内的脯氨酸异构化调节MLL 1的构象，从而破坏PHD 3-Bromo界面并促进MLL 1-PHD 3结构域与CyP 33-RRM结构域的结合。H3 K4 me 3/2和CyP 33-RRM靶向MLL 1-PHD 3的不同表面，并且可以同时结合以形成三元复合物。此外，MLL 1-CyP 33相互作用是体内抑制HOXA 9和HOXC 8基因所必需的。我们的研究结果突出了PHD 3-Bromo盒作为调控平台的作用，通过HDAC募集协调H3 K4 me 3/2标记的MLL 1结合和亲环蛋白介导的抑制。
The MLL1 gene is a frequent target for recurrent chromosomal translocations, resulting in transformation of hematopoietic precursors into leukemia stem cells. Here, we report on structure-function studies that elucidate molecular events in MLL1 binding of histone H3K4me3/2 marks and recruitment of the cyclophilin CyP33. CyP33 contains a PPIase and a RRM domain and regulates MLL1 function through HDAC recruitment. We find that the PPIase domain of CyP33 regulates the conformation of MLL1 through proline isomerization within the PHD3-Bromo linker, thereby disrupting the PHD3-Bromo interface and facilitating binding of the MLL1-PHD3 domain to the CyP33-RRM domain. H3K4me3/2 and CyP33-RRM target different surfaces of MLL1-PHD3 and can bind simultaneously to form a ternary complex. Furthermore, the MLL1-CyP33 interaction is required for repression of HOXA9 and HOXC8 genes in vivo. Our results highlight the role of PHD3-Bromo cassette as a regulatory platform, orchestrating MLL1 binding of H3K4me3/2 marks and cyclophilin-mediated repression through HDAC recruitment.