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A higher-order configuration of the heterodimeric DOT1L–AF10 coiled-coil domains potentiates their leukemogenenic activity
- Source :
- Proceedings of the National Academy of Sciences. 116:19917-19923
- Publication Year :
- 2019
- Publisher :
- Proceedings of the National Academy of Sciences, 2019.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Leucine zipper
Oncogene Proteins, Fusion
Protein domain
Plasma protein binding
Protein Structure, Secondary
03 medical and health sciences
0302 clinical medicine
Protein structure
Protein Domains
Protein Interaction Mapping
Escherichia coli
Humans
Histone octamer
Cell Nucleus
Coiled coil
Leucine Zippers
Leukemia
Multidisciplinary
Gene Expression Regulation, Leukemic
Chemistry
Histone-Lysine N-Methyltransferase
DOT1L
Biological Sciences
Fusion protein
Cell biology
Cell Transformation, Neoplastic
030104 developmental biology
030220 oncology & carcinogenesis
Mutation
Protein Multimerization
Myeloid-Lymphoid Leukemia Protein
Protein Binding
Transcription Factors
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 116
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....7c6b020edea2decc36bfeab1e63df318