Structural basis for activity regulation of MLL family methyltransferases

Abstract

The mixed lineage leukaemia (MLL) family of proteins (including MLL1–MLL4, SET1A and SET1B) specifically methylate histone 3 Lys4, and have pivotal roles in the transcriptional regulation of genes involved in haematopoiesis and development. The methyltransferase activity of MLL1, by itself severely compromised, is stimulated by the three conserved factors WDR5, RBBP5 and ASH2L, which are shared by all MLL family complexes. However, the molecular mechanism of how these factors regulate the activity of MLL proteins still remains poorly understood. Here we show that a minimized human RBBP5–ASH2L heterodimer is the structural unit that interacts with and activates all MLL family histone methyltransferases. Our structural, biochemical and computational analyses reveal a two-step activation mechanism of MLL family proteins. These findings provide unprecedented insights into the common theme and functional plasticity in complex assembly and activity regulation of MLL family methyltransferases, and also suggest a universal regulation mechanism for most histone methyltransferases.

Targeted Disruption of the Interaction between WD-40 Repeat Protein 5 (WDR5) and Mixed Lineage Leukemia (MLL)/SET1 Family Proteins Specifically Inhibits MLL1 and SETd1A Methyltransferase Complexes

“…findings (16,57,58). These results demonstrate the importance of the Win motif for the interaction of WDR5 with each SET1 family core complex but also reveal differences in the role that WDR5 plays in complex stability in vitro.…”

“…However, unlike MLL1, MLL3 does not require interaction with WDR5 to stably interact with RbBP5/ASH2L (16,42,57,58). Furthermore, a recent study suggested that SET1 family members, with the exception of MLL1, do not require WDR5 to assemble a fully functional core complex (57).…”

“…This observation suggests that the requirement of WDR5 for complex assembly may be a convergent property within each subclade, which raises the possibility that different mechanisms may be involved. For example, it was recently shown that substituting MLL1 residues at both positions Asn-3861 and Gln-3867 with the corresponding amino acids in the MLL2 and MLL3 SET domains results in increased interaction with an RbBP5 peptide/ASH2L SPRY domain heterodimer and increased core complex activity in the absence of WDR5 (57). However, variation in the same amino acid positions does not explain the differences in the requirement for WDR5 in the assembly of the human SETd1A and SETd1B complexes, because the amino acids are highly similar in those positions.…”

Bivalent Epigenetic Control of Oncofetal Gene Expression in Cancer

“…Depletion of individual WRAD subunits reduces KMT2 methyltransferase activity, indicating that the SET domain requires WRAD for methyltransferase activity (95)(96)(97). Interaction of KMT2 enzymes with WRAD is mediated via a WIN (WDR5 interacting) motif adjacent to the SET domain (98)(99)(100)(101)(102).…”

Cytogenetic and Molecular Genetic Prognostic Factors of Acute Myeloid Leukemia

“…Ген MLL расположен в локусе 11q23 и кодирует гистон лизин-N-метилтрансферазу, необходимую для глобального контроля метилирования генома и под-держания эпигенетической транскрипционной памяти [88,89].…”