Structure of the leukemia oncogene LMO2: implications for the assembly of a hematopoietic transcription factor complex
Structure of the leukemia oncogene LMO2: implications for the assembly of a hematopoietic transcription factor complex
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DOI：
10.1182/blood-2010-07-293357
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发表时间：
2011-02-17
期刊：
影响因子：
20.3
通讯作者：
Mancini, Erika J.
中科院分区：
文献类型：
--
作者：
El Omari, Kamel;Hoosdally, Sarah J.;Mancini, Erika J.
LIM only蛋白2（LMO 2）是造血干细胞发育的关键调节因子，其在T细胞中的异位表达导致急性淋巴细胞白血病的发作。通过其LIM结构域，LMO 2被认为是DNA结合转录调节因子复合物的支架，包括碱性螺旋-环-螺旋蛋白SCL/TAL 1和E47、锌指蛋白加塔-1和LIM结构域相互作用蛋白LDB 1。为了理解LMO 2在该复合物形成中的作用，并最终剖析其在正常和异常造血中的功能，我们以2.4埃分辨率解析了LMO 2与LDB 1的LID结构域复合的晶体结构。我们观察到一个很大程度上非结构化的LMO 2保持在寄存器的LID绑定两个LIM域。LMO 2的独立确定的晶体结构的比较揭示了LIM域之间的保守铰链周围的大的运动。我们证明，这种构象的灵活性是必要的结合LMO 2，其伴侣蛋白SCL/TAL 1在体外和该复合物在体内的功能。这些结果，连同分子对接和进化上保守的残基的分析，产生的DNA结合复合物的第一个结构模型包含LMO 2，LDB 1，SCL/TAL 1，和加塔-1。（血。2011; 117（7）：2146-2156）
The LIM only protein 2 (LMO2) is a key regulator of hematopoietic stem cell development whose ectopic expression in T cells leads to the onset of acute lymphoblastic leukemia. Through its LIM domains, LMO2 is thought to function as the scaffold for a DNA-binding transcription regulator complex, including the basic helix-loop-helix proteins SCL/TAL1 and E47, the zinc finger protein GATA-1, and LIM-domain interacting protein LDB1. To understand the role of LMO2 in the formation of this complex and ultimately to dissect its function in normal and aberrant hematopoiesis, we solved the crystal structure of LMO2 in complex with the LID domain of LDB1 at 2.4 angstrom resolution. We observe a largely unstructured LMO2 kept in register by the LID binding both LIM domains. Comparison of independently determined crystal structures of LMO2 reveals large movements around a conserved hinge between the LIM domains. We demonstrate that such conformational flexibility is necessary for binding of LMO2 to its partner protein SCL/TAL1 in vitro and for the function of this complex in vivo. These results, together with molecular docking and analysis of evolutionarily conserved residues, yield the first structural model of the DNA-binding complex containing LMO2, LDB1, SCL/TAL1, and GATA-1. (Blood. 2011; 117(7):2146-2156)