Structural basis of CBP/p300 recruitment in leukemia induction by E2A-PBX1
Structural basis of CBP/p300 recruitment in leukemia induction by E2A-PBX1
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DOI：
10.1182/blood-2012-02-411397
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发表时间：
2012-11-08
期刊：
影响因子：
20.3
通讯作者：
Smith, Steven P.
中科院分区：
文献类型：
--
作者：
Denis, Christopher M.;Chitayat, Seth;Smith, Steven P.
E 蛋白是 B 细胞淋巴细胞生成中的关键转录因子。 E2A 是 3 个 E 蛋白编码基因之一，通过参与 1 号染色体易位，与急性淋巴细胞白血病的诱导有关； 19 以及 E2A-PBX1 癌蛋白的后续表达。这种相互作用涉及 E2A-PBX1 N 端转录激活结构域内的一个区域（称为 PCET 基序）和转录共激活因子 CBP/p300 的 KIX 结构域（对于白血病发生至关重要），此前该区域与 E 蛋白沉默有关。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 基序肽和 KIX 结构域之间 1:1 复合物的结构。整个螺旋 PCET 基序中与 KIX 结构域接触的残基对于结合 KIX 和 E2A-PBX1 的骨髓永生化都很重要。这些结果提供了对 E 蛋白驱动的 B 细胞分化和 E 蛋白沉默机制的分子见解，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。 （血。2012；120(19):3968-3977）
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. (Blood. 2012;120(19):3968-3977)