AF10的PZP结构域识别未修饰的H3K27以调控DOT1L介导的H3K79甲基化。
The PZP Domain of AF10 Senses Unmodified H3K27 to Regulate DOT1L-Mediated Methylation of H3K79.
作者信息
Chen Shoudeng, Yang Ze, Wilkinson Alex W, Deshpande Aniruddha J, Sidoli Simone, Krajewski Krzysztof, Strahl Brian D, Garcia Benjamin A, Armstrong Scott A, Patel Dinshaw J, Gozani Or
机构信息
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Department of Biology, Stanford University, Stanford, CA 94305, USA.
出版信息
Mol Cell. 2015 Oct 15;60(2):319-27. doi: 10.1016/j.molcel.2015.08.019. Epub 2015 Oct 1.
AF10, a DOT1L cofactor, is required for H3K79 methylation and cooperates with DOT1L in leukemogenesis. However, the molecular mechanism by which AF10 regulates DOT1L-mediated H3K79 methylation is not clear. Here we report that AF10 contains a "reader" domain that couples unmodified H3K27 recognition to H3K79 methylation. An AF10 region consisting of a PHD finger-Zn knuckle-PHD finger (PZP) folds into a single module that recognizes amino acids 22-27 of H3, and this interaction is abrogated by H3K27 modification. Structural studies reveal that H3 binding triggers rearrangement of the PZP module to form an H3(22-27)-accommodating channel and that the unmodified H3K27 side chain is encased in a compact hydrogen-bond acceptor-lined cage. In cells, PZP recognition of H3 is required for H3K79 dimethylation, expression of DOT1L-target genes, and proliferation of DOT1L-addicted leukemic cells. Together, our results uncover a pivotal role for H3K27-via readout by the AF10 PZP domain-in regulating the cancer-associated enzyme DOT1L.
AF10是一种DOT1L辅因子，是H3K79甲基化所必需的，并在白血病发生过程中与DOT1L协同作用。然而，AF10调节DOT1L介导的H3K79甲基化的分子机制尚不清楚。在此，我们报告AF10包含一个“读取器”结构域，该结构域将未修饰的H3K27识别与H3K79甲基化偶联起来。由一个PHD指-Zn指节-PHD指（PZP）组成的AF10区域折叠成一个单一模块，该模块识别H3的第22-27位氨基酸，并且这种相互作用会被H3K27修饰所消除。结构研究表明，H3结合触发PZP模块重排以形成容纳H3(22-27)的通道，并且未修饰的H3K27侧链被包裹在一个由紧密排列的氢键受体构成的笼状结构中。在细胞中，PZP对H3的识别是H3K79二甲基化、DOT1L靶基因表达以及对DOT1L成瘾的白血病细胞增殖所必需的。总之，我们的结果揭示了H3K27通过AF10 PZP结构域的读出在调节癌症相关酶DOT1L中起关键作用。
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