6ckn
Crystal structure of an AF10 fragment
Structural highlights
DiseaseAF10_HUMAN Precursor T-cell acute lymphoblastic leukemia. A chromosomal aberration involving MLLT10 is associated with acute leukemias. Translocation t(10;11)(p12;q23) with KMT2A/MLL1. The result is a rogue activator protein. A chromosomal aberration involving MLLT10 is associated with diffuse histiocytic lymphomas. Translocation t(10;11)(p13;q14) with PICALM. FunctionAF10_HUMAN Probably involved in transcriptional regulation. In vitro or as fusion protein with KMT2A/MLL1 has transactivation activity. Binds to cruciform DNA.[1] Publication Abstract from PubMedThe mixed-lineage leukemia (MLL)-AF10 fusion oncoprotein recruits DOT1L to the homeobox A (HOXA) gene cluster through its octapeptide motif leucine zipper (OM-LZ), thereby inducing and maintaining the MLL-AF10-associated leukemogenesis. However, the recognition mechanism between DOT1L and MLL-AF10 is unclear. Here, we present the crystal structures of both apo AF10(OM-LZ) and its complex with the coiled-coil domain of DOT1L. Disruption of the DOT1L-AF10 interface abrogates MLL-AF10-associated leukemic transformation. We further show that zinc stabilizes the DOT1L-AF10 complex and may be involved in the regulation of the HOXA gene expression. Our studies may also pave the way for the rational design of therapeutic drugs against MLL-rearranged leukemia. Structural and functional analysis of the DOT1L-AF10 complex reveals mechanistic insights into MLL-AF10-associated leukemogenesis.,Zhang H, Zhou B, Qin S, Xu J, Harding R, Tempel W, Nayak V, Li Y, Loppnau P, Dou Y, Min J Genes Dev. 2018 Mar 1;32(5-6):341-346. doi: 10.1101/gad.311639.118. Epub 2018 Mar, 21. PMID:29563185[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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