Conserved tertiary couplings stabilize elements in the PDZ fold, leading to characteristic patterns of domain conformational flexibility
Conserved tertiary couplings stabilize elements in the PDZ fold, leading to characteristic patterns of domain conformational flexibility
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DOI：
10.1002/pro.318
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发表时间：
2010-03-01
期刊：
影响因子：
8
通讯作者：
Agard, David A.
中科院分区：
文献类型：
--
作者：
Ho, Bosco K.;Agard, David A.
单结构域变构被认为是通过蛋白质结构内的分子内信号传导途径发生的。我们以前通过引入局部热扰动研究了这些途径，并分析了整个蛋白质结构变化的各向异性传播。在这里，我们开发了一种改进的方法，Rotamerically诱导的扰动（RIP），确定强耦合残基之间的热流动的热激发在个别残基的旋转产生的途径进行分析。为了探索这些耦合的性质，我们计算了5个不同PDZ域的完整耦合图。虽然PDZ结构域是一种非常保守的结构折叠，在许多蛋白质-蛋白质复合物中充当支架，但不同的PDZ结构域在响应配体结合时显示出独特的构象灵活性模式：一些在一组α-螺旋中显示出显著的移位，而另一些则没有。耦合图的分析表明计算耦合和观察到的构象灵活性之间的简单关系。在α-螺旋是刚性的结构域中，我们发现α-螺旋与蛋白质主体的偶联，而在具有配体响应性α-螺旋的结构域中，没有发现偶联，这导致了一个模型，其中α-螺旋本质上是动态的，但如果侧链在关键的三级接触处相互作用，则可以被阻尼。这些三级接触相关的统计耦合分析方法确定的高协变接触。由于这些动态模块被各种变构机制所利用，这些三级接触在进化中得到了保护。
Single-domain allostery has been postulated to occur through intramolecular pathways of signaling within a protein structure. We had previously investigated these pathways by introducing a local thermal perturbation and analyzed the anisotropic propagation of structural changes throughout the protein. Here, we develop an improved approach, the Rotamerically Induced Perturbation (RIP), that identifies strong couplings between residues by analyzing the pathways of heat-flow resulting from thermal excitation of rotameric rotations at individual residues. To explore the nature of these couplings, we calculate the complete coupling maps of 5 different PDZ domains. Although the PDZ domain is a well conserved structural fold that serves as a scaffold in many protein-protein complexes, different PDZ domains display unique patterns of conformational flexibility in response to ligand binding: some show a significant shift in a set of alpha-helices, while others do not. Analysis of the coupling maps suggests a simple relationship between the computed couplings and observed conformational flexibility. In domains where the alpha-helices are rigid, we find couplings of the alpha-helices to the body of the protein, whereas in domains having ligand-responsive a-helices, no couplings are found. This leads to a model where the alpha-helices are intrinsically dynamic but can be damped if sidechains interact at key tertiary contacts. These tertiary contacts correlate to high covariation contacts as identified by the statistical coupling analysis method. As these dynamic modules are exploited by various allosteric mechanisms, these tertiary contacts have been conserved by evolution.