6JN2

Crystal structure of the coiled-coil domains of human DOT1L in complex with AF10

Summary for 6JN2

• Entry DOI: 10.2210/pdb6jn2/pdb
• Descriptor: Protein AF-10, Histone-lysine N-methyltransferase, H3 lysine-79 specific (2 entities in total)
• Functional Keywords: hdot1l, haf10, leucine zipper, heterodimer, tetramerization, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 20577.39

Authors

Song, X.,Wang, M.,Yang, N.,Xu, R.M. (deposition date: 2019-03-13, release date: 2019-09-18, Last modification date: 2024-03-27)

Primary citation

Song, X.,Yang, L.,Wang, M.,Gu, Y.,Ye, B.,Fan, Z.,Xu, R.M.,Yang, N.
A higher-order configuration of the heterodimeric DOT1L-AF10 coiled-coil domains potentiates their leukemogenenic activity.
Proc.Natl.Acad.Sci.USA, 116:19917-19923, 2019

PubMed Abstract: Chromosomal translocations of (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.

PubMed: 31527241
DOI: 10.1073/pnas.1904672116

Experimental method

X-RAY DIFFRACTION (3.6 Å)