Zhou Zhechong, Kang Sisi, Huang Zhaoxia, Zhou Ziliang, Chen Shoudeng
Molecular Imaging Center, Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.
J Leukoc Biol. 2021 Dec;110(6):1091-1099. doi: 10.1002/JLB.1MA0421-010R. Epub 2021 May 16.
The interaction of the solo H3K79 methyltransferase DOT1-like (DOT1L) and its regulatory factor ALL1-fused gene from chromosome 10 protein (AF10) is crucial for the transcription of developmental genes such as HOXA in acute leukemia. The octapeptide motif and leucine zipper region of AF10 is responsible for binding DOT1L and catalyzing H3K79 monomethylation to demethylation. However, the characteristics of the mechanism between DOT1L and AF10 are not clear. Here, we present the crystal structures of coiled-coil regions of DOT1L-AF10 and AF10-inhibitory peptide, demonstrating the inhibitory peptide could form a compact complex with AF10 via a different recognition pattern. Furthermore, an inhibitory peptide with structure-based optimization is identified and decreases the HOXA gene expression in a human cell line. Our studies provide an innovative pharmacologic basis for therapeutic intervention in leukemia.
在急性白血病中，单拷贝H3K79甲基转移酶类DOT1样蛋白（DOT1L）与其调控因子10号染色体上的ALL1融合基因蛋白（AF10）之间的相互作用对于HOXA等发育基因的转录至关重要。AF10的八肽基序和亮氨酸拉链区域负责结合DOT1L并催化H3K79单甲基化向去甲基化的转变。然而，DOT1L与AF10之间机制的特点尚不清楚。在此，我们展示了DOT1L-AF10卷曲螺旋区域和AF10抑制肽的晶体结构，表明抑制肽可通过不同的识别模式与AF10形成紧密复合物。此外，鉴定出一种经过基于结构优化的抑制肽，其可降低人细胞系中HOXA基因的表达。我们的研究为白血病的治疗干预提供了创新的药理学基础。
