Department of Computational & Structural Biology, Max F. Perutz Laboratories, Campus Vienna Biocenter 5, A-1030 Vienna, Austria.
J Am Chem Soc. 2009 Mar 4;131(8):3063-8. doi: 10.1021/ja809947w.
Allosteric regulation is an effective mechanism of control in biological processes. In allosteric proteins a signal originating at one site in the molecule is communicated through the protein structure to trigger a specific response at a remote site. Using NMR relaxation dispersion techniques we directly observe the dynamic process through which the KIX domain of CREB binding protein communicates allosteric information between binding sites. KIX mediates cooperativity between pairs of transcription factors through binding to two distinct interaction surfaces in an allosteric manner. We show that binding the activation domain of the mixed lineage leukemia (MLL) transcription factor to KIX induces a redistribution of the relative populations of KIX conformations toward a high-energy state in which the allosterically activated second binding site is already preformed, consistent with the Monod-Wyman-Changeux (WMC) model of allostery. The structural rearrangement process that links the two conformers and by which allosteric information is communicated occurs with a time constant of 3 ms at 27 degrees C. Our dynamic NMR data reveal that an evolutionarily conserved network of hydrophobic amino acids constitutes the pathway through which information is transmitted.
变构调节是生物过程中一种有效的控制机制。在变构蛋白中，分子中一个位点的信号通过蛋白质结构传递，从而在远程位点引发特定的反应。我们使用 NMR 弛豫弥散技术直接观察到 CREB 结合蛋白的 KIX 结构域在结合位点之间传递变构信息的动态过程。KIX 通过以变构方式结合两个不同的相互作用表面，介导转录因子对之间的协同作用。我们表明，混合谱系白血病（MLL）转录因子的激活结构域与 KIX 的结合诱导 KIX 构象的相对种群向高能状态重新分布，其中变构激活的第二个结合位点已经预先形成，与变构的 Monod-Wyman-Changeux（WMC）模型一致。连接两个构象体并传递变构信息的结构重排过程在 27°C 时的时间常数为 3 毫秒。我们的动态 NMR 数据显示，一个进化上保守的疏水性氨基酸网络构成了信息传递的途径。
