Crystal Structure of MLL2 Complex Guides the Identification of a Methylation Site on P53 Catalyzed by KMT2 Family Methyltransferases
Crystal Structure of MLL2 Complex Guides the Identification of a Methylation Site on P53 Catalyzed by KMT2 Family Methyltransferases
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MLL2 复合物的晶体结构指导 KMT2 家族甲基转移酶催化的 P53 甲基化位点的识别
DOI：
10.1016/j.str.2020.07.002
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发表时间：
2020-10-06
期刊：
影响因子：
5.7
通讯作者：
Chen, Yong
中科院分区：
文献类型：
--
作者：
Li, Yanjing;Zhao, Lijie;Chen, Yong
KMT2家族甲基转移酶使组蛋白H3赖氨酸4甲基化，并在多种细胞过程中发挥重要作用。MLL2 （KMT2B）是发育过程中早期表观遗传决策所必需的，并有助于二价启动子的甲基化。在这里，我们确定了MLL2(SET)-RBBP5(AS-ABM)-ASH2L（SPRY）复合物的晶体结构，并证实RBBP5(AS-ABM)-ASH2L（SPRY）是通过KMT2家族复合物的保守机制激活MLL2 SET结构域所必需的。在MLL2复合物结构中，MLL2（SET）的短n端环采用与H3肽相似的构型，插入到另一个MLL2（SET）的底物结合口袋中，表明MLL2（SET）的潜在底物。我们发现P53包含一个类似于MLL2 n端环（SET）的序列，并证明P53的K305可以被KMT2家族复合物甲基化，除了SET1A。我们的研究结果为P53和KMT2家族复合物之间的功能相互作用提供了重要的启示，也提示了KMT2家族甲基转移酶的非组蛋白底物可能广泛存在。
KMT2 family methyltransferases methylate histone H3 lysine 4 and play essential roles inmultiple cellular processes. MLL2 (KMT2B) is required for early epigenetic decisions during development and contributes to the methylation of bivalent promoters. Here, we determined the crystal structure of the MLL2(SET)-RBBP5(AS-ABM)-ASH2L(SPRY) complex and confirmed that RBBP5(AS-ABM)-ASH2L(SPRY) was essential for activating the MLL2 SET domain through a conserved mechanism across KMT2 family complexes. In the MLL2 complex structure, a short N-terminal loop of MLL2(SET) adopts a similar configuration of the H3 peptide and inserts into the substrate-binding pocket of another MLL2(SET), indicating a potential substrate for MLL2(SET). We identify that P53 contains a sequence similar to the N-terminal loop of MLL2(SET), and demonstrate that K305 of P53 could be methylated by KMT2 family complexes except for SET1A. Our results provide an important implication of functional interplay between P53 and KMT2 family complexes, and also suggest the possible broad land-scape of non-histone substrate for KMT2 family methyltransferases.