KMT2 family methyltransferases methylate histone H3 lysine 4 and play essential roles in multiple 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 landscape of non-histone substrate for KMT2 family methyltransferases.

KMT2 家族甲基转移酶甲基化组蛋白 H3 赖氨酸 4，并在多个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定所必需的，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，并确认 RBBP5 _AS-ABM -ASH2L _SPRY通过跨 KMT2 家族复合物的保守机制激活 MLL2 SET 域是必不可少的。在 MLL2 复合体结构中，MLL2 _{SET 的}一个短 N 端环采用与 H3 肽相似的构型并插入另一个 MLL2 _SET的底物结合口袋中，表明 MLL2 _SET的潜在底物。我们确定 P53 包含类似于 MLL2 _SET的 N 端环的序列，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意义，并且还表明 KMT2 家族甲基转移酶的非组蛋白底物可能存在广泛的前景。