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首页> 外文期刊>Journal of Molecular Biology >The dimerization domain of HNF-1 alpha: Structure and plasticity of anintertwined four-helix bundle with application to diabetes mellitus
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The dimerization domain of HNF-1 alpha: Structure and plasticity of anintertwined four-helix bundle with application to diabetes mellitus

机译：HNF-1α的二聚化域：缠结的四螺旋束的结构和可塑性及其在糖尿病中的应用

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Maturity-onset diabetes mellitus of the young (MODY) is a human genetic syndrome most commonly due to mutations in hepatocyte nuclear factor-1 alpha (HNF-1 alpha). Here, we describe the crystal structure of the HNF-1 alpha dimerization domain at 1.7 Angstrom, resolution and assess its structural plasticity. The crystal's low solvent content (23 %, v/v) leads to tight packing of peptides in the lattice. Two independent dimers, similar in structure, are formed in the unit cell by a 2-fold crystallographic symmetry axis. The dimers define a novel intertwined four-helix bundle (4HB). Each protomer contains two alpha -helices separated by a sharp non-canonical turn. Dimer-related alpha -helices form anti-parallel coiled-coils, including an N-terminal "mini-zipper" complementary in structure, symmetry and surface characteristics to transcriptional coactivator dimerization cofactor of HNF-1 (DCoH). A confluence of ten leucine side-chains (five per protomer) forms a hydrophobic core. Isotope-assisted NMR studies demonstrate that a similar intertwined dimer exists in solution. Comparison of structures obtained in multiple independent crystal forms indicates that the mini-zipper is a stable structural element, whereas the C-terminal cc-helix can adopt a broad range of orientations. Segmental alignment of the mini-zipper (mean pairwise root-mean-square difference (rmsd) in C-alpha coordinates of 0.29 Angstrom) is associated with a 2.1 Angstrom mean C-alpha rmsd displacement of the C-terminal coiled-coil. The greatest C-terminal structural variation (4.1 Angstrom C-alpha rmsd displacement) is observed in the DCoH-bound peptide. Diabetes-associated mutations perturb distinct structural features of the HNF-1 alpha domain. One mutation (L12H) destabilizes the domain but preserves structural specificity. Adjoining H12 side-chains in a native-like dimer are predicted to alter the functional surface of the mini-zipper involved in DCoH recognition. The other mutation (C20R), by contrast, leads to a dimeric molten globule, as indicated by its H-1-NMR features and fluorescent binding of 1-anilino-8-naphthalene sulfonate. We propose that a glycine-specific turn configuration enables specific interactions between the mini-zipper and the C-terminal coiled-toil.
机译：年轻人的成熟期糖尿病（MODY）是人类遗传综合症，最常见的原因是肝细胞核因子-1α（HNF-1 alpha）突变。在这里，我们描述了HNF-1α二聚结构域在1.7埃时的晶体结构，分辨率并评估了其结构可塑性。晶体的低溶剂含量（23％，v / v）导致肽在晶格中紧密堆积。通过2倍晶体学对称轴在单位晶格中形成结构相似的两个独立的二聚体。二聚体定义了一种新型的交织的四螺旋束（4HB）。每个protomer包含两个由尖锐的非规范转弯隔开的α螺旋。与二聚体有关的α-螺旋形成反平行的卷曲螺旋，包括与HNF-1（DCoH）的转录共激活因子二聚化辅因子在结构，对称性和表面特征上互补的N末端“微型拉链”。十条亮氨酸侧链的融合（每个原核细胞有五个）形成一个疏水核心。同位素辅助的NMR研究表明，溶液中存在相似的缠绕二聚体。比较以多种独立晶体形式获得的结构表明，迷你拉链是稳定的结构元素，而C端cc螺旋可以采用多种取向。迷你拉链的分段对齐（在C-alpha坐标中平均成对的均方根差（rmsd）为0.29埃）与C末端卷曲线圈的2.1埃平均C-alpha rmsd位移相关。在与DCoH结合的肽中观察到最大的C末端结构变异（4.1埃C-αrmsd位移）。糖尿病相关突变扰乱了HNF-1α结构域的独特结构特征。一个突变（L12H）使结构域不稳定，但保留了结构特异性。预计在类似天然的二聚体中邻接的H12侧链会改变参与DCoH识别的迷你拉链的功能表面。相比之下，另一个突变（C20R）导致二聚体熔融小球，如其H-1-NMR特征和1-苯胺基-8-萘磺酸盐的荧光结合所表明的。我们建议甘氨酸特定的转弯配置使迷你拉链和C末端线圈之间的特定相互作用成为可能。

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