MLLs Bind Differently to Nucleosomes with Ubiquitinated Histone H2B

Mutations or genomic rearrangements involving mixed-lineage leukemia (MLL) methyltransferases can contribute to the development of aggressive leukemias. MLLs are known to methylate histone H3 at tail residue K4, creating an epigenetic mark associated with open chromatin and active transcription, but the mechanism of this methylation is poorly understood. Using cryo-electron microscopy (cryo-EM), Xue, Yao, and colleagues determined the structure of MLL1 in complex with a nucleosome core particle (NCP) containing monoubiquitinated H2B^K120 (ubNCP), a modification that stimulates MLLs' methyltransferase activity, as well as structures of MLL1 in complex with an unmodified NCP. Three-dimensional classification revealed that MLL1–NCP exhibited two binding modes (binding modes 1 and 2), with binding mode 2 being characterized by a rotation of the MLL1 complex around the nucleosome surface that shifts MLL1′s catalytic SET domain away from its substrate, the tail of H3, suggesting that binding mode 2 may represent an inactive state. In contrast, MLL1–ubNCP exhibited only binding mode 1, implying that MLL1 may alternate between the two binding modes when in contact with unmodified histones. Congruently, the catalytic efficiency of MLL1 given ubNCP as a substrate was twofold higher than the catalytic efficiency when unmodified NCP was the substrate. Additionally, cryo-EM was used to solve the structure of the related MLL3 in complex with ubNCP, revealing that the binding mode of MLL3–ubNCP is similar to that of MLL1–ubNCP, with some rearrangements affecting the MLL-associated regulatory proteins WDR5 and RBBP5 and their interactions with MLL1′s or MLL3′s catalytic SET domain. Together, these findings provide the foundation for understanding the mechanism of MLLs' methyltransferase activity, an important aspect of understanding their role in cancer pathogenesis.

Xue H, Yao T, Cao M, Zhu G, Li Y, Yuan G, et al. Structural basis of nucleosome recognition and modification by MLL methyltransferases. Nature 2019 Sep 4 [Epub ahead of print].

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