Structural basis for the recognition of ldb1 by the N-terminal LIM domains of LMO2 and LMO4
Structural basis for the recognition of ldb1 by the N-terminal LIM domains of LMO2 and LMO4
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DOI：
10.1093/emboj/cdg196
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发表时间：
2003-05-01
期刊：
影响因子：
11.4
通讯作者：
Matthews, JM
中科院分区：
文献类型：
--
作者：
Deane, JE;Mackay, JP;Matthews, JM
LMO2和LMO4是核转录调节小家族的成员，对正常发育和疾病过程都很重要。LMO2对造血和血管生成是必不可少的，该蛋白的不适当过度表达会导致T细胞白血病。LMO4在乳腺中受发育调节，与乳腺肿瘤的发生有关。这两种蛋白质都包含两个重复的LIM结构域。LMO2和LMO4与普遍存在的核适配蛋白LDB1/NLI/CLIM2相互作用，LDB1/NLI/CLIM2通过LIM相互作用结构域(LDB1-LID)与LMO和LIM同源结构域蛋白的LIM结构域结合。我们报道了两个LMO：LDB1配合物(PDB：1M3V和1J2O)的溶液结构，结果表明LDB1-LID以扩展的构象结合到LMO2和LMO4的N-末端LIM结构域(LIM1)，在LIM1结构域中贡献了第三链的β-发夹。这些发现构成了LIM介导的蛋白质-蛋白质相互作用的第一个分子定义，并表明了LDB1可以结合各种具有低序列同源性的LIM结构域的机制。
LMO2 and LMO4 are members of a small family of nuclear transcriptional regulators that are important for both normal development and disease processes. LMO2 is essential for hemopoiesis and angiogenesis, and inappropriate overexpression of this protein leads to T-cell leukemias. LMO4 is developmentally regulated in the mammary gland and has been implicated in breast oncogenesis. Both proteins comprise two tandemly repeated LIM domains. LMO2 and LMO4 interact with the ubiquitous nuclear adaptor protein ldb1/NLI/CLIM2, which associates with the LIM domains of LMO and LIM homeodomain proteins via its LIM interaction domain (ldb1-LID). We report the solution structures of two LMO:ldb1 complexes (PDB: 1M3V and 1J2O) and show that ldb1-LID binds to the N-terminal LIM domain (LIM1) of LMO2 and LMO4 in an extended conformation, contributing a third strand to a beta-hairpin in LIM1 domains. These findings constitute the first molecular definition of LIM-mediated protein-protein interactions and suggest a mechanism by which ldb1 can bind a variety of LIM domains that share low sequence homology.