A higher-order configuration of the heterodimeric DOT1L–AF10 coiled-coil domains potentiates their leukemogenenic activity
2019
Chromosomal translocationsof MLL1 (Mixed Lineage Leukemia 1) yield oncogenic chimeric proteins containing the N-terminal portion of MLL1 fused with distinct partners. The MLL1–AF10 fusion causes leukemia through recruiting the H3K79
histone methyltransferase
DOT1Lvia AF10’s octapeptide and
leucine zipper(OM-LZ) motifs. Yet, the precise interaction sites in
DOT1L, detailed interaction modes between AF10 and
DOT1L, and the functional configuration of MLL1–AF10 in leukeomogenesis remain unknown. Through a combined approach of structural and functional analyses, we found that the LZ domain of AF10 interacts with the
coiled-coildomains of
DOT1Lthrough a conserved binding mode and discovered that the C-terminal end of the LZ domain and the OM domain of AF10 mediate the formation of a
DOT1L–AF10 octamer via tetramerization of the binary complex. We reveal that the oligomerization ability of the
DOT1L–AF10 complex is essential for MLL1–AF10’s leukemogenic function. These findings provide insights into the molecular basis of pathogenesis by MLL1 rearrangements.
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