Multistate structures of the MLL1-WRAD complex bound to H2B-ubiquitinated nucleosome

The human Mixed Lineage Leukemia-1 (MLL1) complex orchestrates methylation of histone H3K4 to promote transcription and is the target of chromosomal translocations in a variety of leukemias. The MLL1 core complex comprises the MLL1 methyltransferase and the WRAD complex, which contains WDR5, RbBp5, Ash2L, and DPY-30. Recent studies have shed light on the structure and organization of the human MLL1-WRAD complex bound to nucleosomes but were not able to resolve portions of the Ash2L subunit or DPY30. We used an integrated approach combining cryo-electron microscopy and mass spectrometry-cross linking to obtain models of the MLL1-WRAD complex bound to nucleosomes containing monoubiquitinated histone H2B, which is reported to stimulate H3K4 methylation. We constructed a model containing the Ash2L intrinsically disordered region (IDR), SPRY insertion region, and Sdc1-DPY30 interacting region (SDI-motif), as well as the DPY30 dimer, which were not resolved in previous structures. In addition to the model of the active state, we resolved three additional states of MLL1-WRAD lacking one or more subunits that may reflect different steps in the assembly of MLL1-WRAD. Our results provide a more complete picture of MLL1-WRAD and how it assembles on nucleosomes to form an active methyltransferase complex.