Allosteric communication in the KIX domain proceeds through dynamic repacking of the hydrophobic core.
Allosteric communication in the KIX domain proceeds through dynamic repacking of the hydrophobic core.
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DOI：
10.1021/cb4002188
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发表时间：
2013-07-19
影响因子：
4
通讯作者：
Tollinger, Martin
中科院分区：
文献类型：
--
作者：
Bruschweiler, Sven;Konrat, Robert;Tollinger, Martin
转录辅激活因子CREB结合蛋白（CBP）的KIX结构域协同介导转录因子之间的相互作用。转录因子混合谱系白血病（MLL）的结合诱导KIX低密度构象的形成，该构象类似于第二转录因子分子存在时KIX结构域的构象。核磁共振自旋弛豫研究先前表明，变构偶联是通过一个疏水核心残基网络进行的，该网络连接了两个结合位点。本文描述了KIX与MLL二元配合物的高分辨率NMR溶液结构，以及由MLL和磷酸化激酶诱导结构域CREB （pKID）作为第二配体形成的KIX三元配合物。我们发现pKID与KIX与MLL的二元配合物的结合伴随着蛋白疏水核心的变构网络的重新包装。源自甲基13C化学位移的旋回体居群揭示了结构坐标未捕获的对重新包装过程的动态贡献，并举例说明了KIX结构域变构通信的动态性质。
The KIX domain of the transcriptional coactivator CREB binding protein (CBP) co-operatively mediates interactions between transcription factors. Binding of the transcription factor mixed-lineage leukemia (MLL) induces the formation of a low-populated conformer of KIX that resembles the conformation of the KIX domain in the presence of a second transcription factor molecule. NMR spin relaxation studies have previously shown that allosteric coupling proceeds through a network of hydrophobic core residues that bridge the two binding sites. Here we describe high-resolution NMR solution structures of the binary complex of KIX with MLL and the ternary complex of KIX formed with MLL and phosphorylated kinase inducible domain of CREB (pKID) as a second ligand. We show that binding of pKID to the binary complex of KIX with MLL is accompanied by a defined repacking of the allosteric network in the hydrophobic core of the protein. Rotamer populations derived from methyl group 13C chemical shifts reveal a dynamic contribution to the repacking process that is not captured by the structural coordinates and exemplify the dynamic nature of allosteric communication in the KIX domain.