Crystal structure of human LDB1 in complex with SSBP2.
Crystal structure of human LDB1 in complex with SSBP2.
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人 LDB1 与 SSBP2 复合物的晶体结构。
DOI：
10.1073/pnas.1914181117
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发表时间：
2020
影响因子：
11.1
通讯作者：
Xu Wenqing
中科院分区：
文献类型：
--
作者：
Wang Hongyang;Kim Juhyun;Wang Zhizhi;Yan Xiao-Xue;Dean Ann;Xu Wenqing
LIM结构域结合蛋白(人类中的LDB1和LDB2，果蝇中的ChIP)通过与多种LIM同源盒和LIM-Only蛋白在心脏发生、神经发生和造血等不同发育系统中合作，在细胞命运决定中发挥关键作用。在哺乳动物的红系细胞中，LDB1二聚体支持增强子和红细胞生成相关基因之间的远程连接，包括β-珠蛋白基因。单链DNA结合蛋白(SSBPs)与LDB蛋白的LDB/Chip保守结构域(LCD)特异性结合，通过阻止蛋白酶体降解来稳定LDB，从而促进其在基因调控中的功能。LDB1与SSBPs的自身相互作用和界面的结构基础尚不清楚。在这里，我们报道了人的LDB1/SSBP2络合物的2.8°分辨率的晶体结构。LDB1二聚化结构域(DD)包含一个N-末端核运输因子2(NTF2)亚域和一个小的螺旋4-螺旋5亚域，它们共同形成了LDB1二聚化界面。对称LDB1二聚体中的2个LCDs位于核心DDS的两侧，每个LCCDs与SSBP2二聚体形成广泛的相互作用。LDB1 DD和LCD之间的保守连接子覆盖了LDB1 NTF2样亚域的一个潜在的配体结合口袋，可能是LDB1结构和功能的调节位点。我们的结构和生化数据为理解LDB1和LDB1/SSBP相互作用如何形成各种复合体的结构核心提供了备受期待的结构基础，这些复合体介导细胞选择决定和长程增强子-启动子相互作用。
The Lim domain binding proteins (LDB1 and LDB2 in human and Chip inDrosophila) play critical roles in cell fate decisions through partnership with multiple Lim-homeobox and Lim-only proteins in diverse developmental systems including cardiogenesis, neurogenesis, and hematopoiesis. In mammalian erythroid cells, LDB1 dimerization supports long-range connections between enhancers and genes involved in erythropoiesis, including the β-globin genes. Single-stranded DNA binding proteins (SSBPs) interact specifically with the LDB/Chip conserved domain (LCCD) of LDB proteins and stabilize LDBs by preventing their proteasomal degradation, thus promoting their functions in gene regulation. The structural basis for LDB1 self-interaction and interface with SSBPs is unclear. Here we report a crystal structure of the human LDB1/SSBP2 complex at 2.8-Å resolution. The LDB1 dimerization domain (DD) contains an N-terminal nuclear transport factor 2 (NTF2)-like subdomain and a small helix 4–helix 5 subdomain, which together form the LDB1 dimerization interface. The 2 LCCDs in the symmetric LDB1 dimer flank the core DDs, with each LCCD forming extensive interactions with an SSBP2 dimer. The conserved linker between LDB1 DD and LCCD covers a potential ligand-binding pocket of the LDB1 NTF2-like subdomain and may serve as a regulatory site for LDB1 structure and function. Our structural and biochemical data provide a much-anticipated structural basis for understanding how LDB1 and the LDB1/SSBP interactions form the structural core of diverse complexes mediating cell choice decisions and long-range enhancer–promoter interactions.