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 abrogated 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：

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PALI1和JARID2之间的融合进化导致PRC2的变构激活

聚梳抑制复合物2（PRC2）是一种组蛋白甲基转移酶，可维持细胞身份。JARID2是PRC2唯一已知触发甲基转移酶的变构活化的辅助亚基。但是，该机制不能推广到所有PRC2变体，因为在脊椎动物中，JARID2与PRC2的大多数辅助亚单位互斥。在这里，我们提供功能和结构上的证据，表明脊椎动物特异性的PRC2辅助亚基PALI1是通过在分子水平上模仿JARID2的趋同进化而出现的。机械上，PRC2使PALI1 K1241甲基化，然后与PRC2调节亚基EED结合，以变构方式激活PRC2。PALI1 K1241在小鼠和人类细胞系中甲基化，对于PALI1诱导PRC2的变构活化至关重要。高分辨率晶体结构显示，PALI1模仿了JARID2和EED之间形成的调节相互作用。独立地，PALI1还促进PRC2与DNA和核小体的结合。在急性粒细胞性白血病细胞中，PALI1的过表达导致细胞分化，其表型因功能分离的PALI1突变而被废除，其变构激活性缺陷并具有DNA结合活性。总的来说，我们表明PALI1促进了PRC2的催化作用和底物结合，并提供了亚基诱导的变构活化是holo-PRC2复合物的一般特性的证据。具有功能分离的PALI1突变废除的表型，在变构激活方面有缺陷，并且在DNA结合方面具有活性。总的来说，我们表明PALI1促进了PRC2的催化作用和底物结合，并提供了亚基诱导的变构活化是holo-PRC2复合物的一般特性的证据。具有功能分离的PALI1突变废除的表型，在变构激活方面有缺陷，并且在DNA结合方面具有活性。总的来说，我们表明PALI1促进了PRC2的催化作用和底物结合，并提供了亚基诱导的变构活化是holo-PRC2复合物的一般特性的证据。