A tryptophan-phenylalanine binding motif for the histone methyltransferases MLL4 and MLL3.

The human methyltransferases mixed lineage leukemia 4 and 3 (MLL4 and MLL3) play pivotal roles in the regulation of epigenetic and transcriptional programs. Here, we report the identification and characterization of a tryptophan-phenylalanine binding motif recognized by MLL4 and MLL3. Binding of the sixth PHD finger of MLL4 and the seventh PHD finger of MLL3 to the tryptophan-phenylalanine motif derived from a set of human proteins was detected in a proteomic peptide-phage screening of intrinsically disordered regions of the human proteome and confirmed in NMR and MST assays. Mutational, genetic and binding interface analyses reveal the molecular mechanism underlying the direct interaction of MLL4 and MLL3 with the motif. A high correlation of expression of MLL4/MLL3 and the motif containing proteins in several tumor types suggests shared roles in oncogenic transcriptional programs. In conclusion, our findings highlight a potential relationship between the MLL4/MLL3 methyltransferases and diverse motif-containing epigenetic coregulators.