A higher-order configuration of the heterodimeric DOT1L-AF10 coiled-coil domains potentiates their leukemogenenic activity.

Chromosomal translocations of 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 DOT1L via 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-coil domains of DOT1L through 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.
Mesh Terms:
Cell Nucleus, Cell Transformation, Neoplastic, Escherichia coli, Gene Expression Regulation, Leukemic, Histone-Lysine N-Methyltransferase, Humans, Leucine Zippers, Leukemia, Mutation, Myeloid-Lymphoid Leukemia Protein, Oncogene Proteins, Fusion, Protein Binding, Protein Domains, Protein Interaction Mapping, Protein Multimerization, Protein Structure, Secondary, Transcription Factors
Proc Natl Acad Sci U S A
Date: Oct. 01, 2019
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