Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
Blood. 2012 Nov 8;120(19):3968-77. doi: 10.1182/blood-2012-02-411397. Epub 2012 Sep 12.
E-proteins are critical transcription factors in B-cell lymphopoiesis. E2A, 1 of 3 E-protein-encoding genes, is implicated in the induction of acute lymphoblastic leukemia through its involvement in the chromosomal translocation 1;19 and consequent expression of the E2A-PBX1 oncoprotein. An interaction involving a region within the N-terminal transcriptional activation domain of E2A-PBX1, termed the PCET motif, which has previously been implicated in E-protein silencing, and the KIX domain of the transcriptional coactivator CBP/p300, critical for leukemogenesis. However, the structural details of this interaction remain unknown. Here we report the structure of a 1:1 complex between PCET motif peptide and the KIX domain. Residues throughout the helical PCET motif that contact the KIX domain are important for both binding KIX and bone marrow immortalization by E2A-PBX1. These results provide molecular insights into E-protein-driven differentiation of B-cells and the mechanism of E-protein silencing, and reveal the PCET/KIX interaction as a therapeutic target for E2A-PBX1-induced leukemia.
E 蛋白是 B 细胞淋巴发生中的关键转录因子。E2A 是编码 E 蛋白的 3 个基因之一，通过参与染色体易位 1;19 和随后表达 E2A-PBX1 癌蛋白，参与诱导急性淋巴细胞白血病。涉及 E2A-PBX1 N 端转录激活结构域内区域的相互作用，称为 PCET 基序，先前已涉及 E 蛋白沉默，以及转录共激活因子 CBP/p300 的 KIX 结构域，对于白血病的发生至关重要。然而，这种相互作用的结构细节仍然未知。在这里，我们报告了 PCET 基序肽与 KIX 结构域之间 1:1 复合物的结构。与 KIX 结构域接触的整个螺旋 PCET 基序的残基对于结合 KIX 和 E2A-PBX1 诱导的骨髓永生化都很重要。这些结果为 E 蛋白驱动的 B 细胞分化和 E 蛋白沉默的机制提供了分子见解，并揭示了 PCET/KIX 相互作用作为 E2A-PBX1 诱导的白血病的治疗靶点。
