Menin-MLL1 complex

The Menin-MLL1 complex is a protein-protein interaction between menin, a scaffold protein encoded by the MEN1 gene, and Mixed Lineage Leukemia 1 (MLL1), a histone H3 lysine 4 (H3K4) methyltransferase that functions as a transcriptional co-activator. Menin tethers MLL1 to chromatin promoters, facilitating assembly of the MLL1 core complex (including WDR5, RbBP5, Ash2L, DPY-30) via the MLL1 Win motif binding to WDR5, which enables mono-, di-, and trimethylation of H3K4 to maintain active gene expression, such as Hox genes. MLL1 is proteolytically processed into MLL-N and MLL-C fragments that reassociate, with domains like CXXC for DNA binding, SET for methyltransferase activity, and motifs for cofactor interactions. The interaction involves MLL1's N-terminal menin-binding motifs (MBM1: MLL4-15, MBM2: MLL23-43) binding menin's deep pocket with high affinity (Kd=6.8 nM). This complex drives leukemogenesis in MLL1-translocated acute leukemias and solid tumors, acting as a therapeutic target for small-molecule inhibitors that block the interface.[1][2][3][5]

Other names

Menin/MLL1 interactionmenin-MLL complexMLL1-menin complex

Inhibition of menin-MLL1 protein-protein interaction, Disruption of H3K4 methylation, Prevention of MLL1 core complex assembly