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PALI1 facilitates DNA and nucleosome binding by PRC2 and triggers an allosteric activation of catalysis
Nature Communications ( IF 16.6 ) Pub Date : 2021-07-28 , DOI: 10.1038/s41467-021-24866-3
Qi Zhang 1 , Samuel C Agius 1 , Sarena F Flanigan 1 , Michael Uckelmann 1 , Vitalina Levina 1 , Brady M Owen 1 , Chen Davidovich 1, 2
Affiliation  

The polycomb repressive complex 2 (PRC2) is a histone methyltransferase that maintains cell identities. JARID2 is the only accessory subunit of PRC2 that known to trigger an allosteric activation of methyltransferase. Yet, this mechanism cannot be generalised to all PRC2 variants as, in vertebrates, JARID2 is mutually exclusive with most of the accessory subunits of PRC2. Here we provide functional and structural evidence that the vertebrate-specific PRC2 accessory subunit PALI1 emerged through a convergent evolution to mimic JARID2 at the molecular level. Mechanistically, PRC2 methylates PALI1 K1241, which then binds to the PRC2-regulatory subunit EED to allosterically activate PRC2. PALI1 K1241 is methylated in mouse and human cell lines and is essential for PALI1-induced allosteric activation of PRC2. High-resolution crystal structures revealed that PALI1 mimics the regulatory interactions formed between JARID2 and EED. Independently, PALI1 also facilitates DNA and nucleosome binding by PRC2. In acute myelogenous leukemia cells, overexpression of PALI1 leads to cell differentiation, with the phenotype altered by a separation-of-function PALI1 mutation, defective in allosteric activation and active in DNA binding. Collectively, we show that PALI1 facilitates catalysis and substrate binding by PRC2 and provide evidence that subunit-induced allosteric activation is a general property of holo-PRC2 complexes.



中文翻译:

PALI1通过PRC2促进DNA和核小体结合并触发催化的变构激活

多梳抑制复合物 2 (PRC2) 是一种组蛋白甲基转移酶,可维持细胞身份。JARID2 是PRC2 的唯一辅助亚基,已知可触发甲基转移酶的变构激活。然而,这种机制不能推广到所有 PRC2 变体,因为在脊椎动物中,JARID2 与 PRC2 的大多数附属亚基是相互排斥的。在这里,我们提供了功能和结构证据,表明脊椎动物特定的 PRC2 辅助亚基 PALI1 通过趋同进化出现,以在分子水平上模拟 JARID2。从机制上讲,PRC2 甲基化 PALI1 K1241,然后结合到 PRC2 调节亚基 EED 以变构激活 PRC2。PALI1 K1241 在小鼠和人类细胞系中被甲基化,对于 PALI1 诱导的 PRC2 变构激活至关重要。高分辨率晶体结构显示 PALI1 模拟 JARID2 和 EED 之间形成的调节相互作用。独立地,PALI1 还促进了 PCR2 与 DNA 和核小体的结合。在急性髓性白血病细胞中,PALI1 的过表达导致细胞分化,表型因功能分离的 PALI1 突变而改变,变构激活有缺陷,DNA 结合活跃。总的来说,我们表明 PALI1 促进了 PRC2 的催化和底物结合,并提供了亚基诱导的变构激活是全息-PRC2 复合物的一般特性的证据。表型因功能分离 PALI1 突变而改变,变构激活有缺陷,DNA 结合活跃。总的来说,我们表明 PALI1 促进了 PRC2 的催化和底物结合,并提供了亚基诱导的变构激活是全息-PRC2 复合物的一般特性的证据。表型因功能分离 PALI1 突变而改变,变构激活有缺陷,DNA 结合活跃。总的来说,我们表明 PALI1 促进了 PRC2 的催化和底物结合,并提供了亚基诱导的变构激活是全息-PRC2 复合物的一般特性的证据。

更新日期:2021-07-28
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