Evaluation of energetic and dynamic coupling networks in a PDZ domain protein
Evaluation of energetic and dynamic coupling networks in a PDZ domain protein
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DOI：
10.1016/j.jmb.2006.08.076
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发表时间：
2006-12-01
影响因子：
5.6
通讯作者：
Lee, Andrew L.
中科院分区：
文献类型：
--
作者：
Fuentes, Ernesto J.;Gilmore, Steven A.;Lee, Andrew L.
大量的计算和实验研究已经确定了分子内通讯的“途径”或“网络”的重要性，传播变构。在这里，我们已经使用诱变和NMR弛豫方法来调查的范围和性质的通信网络中发现的第二突触后密度-95/光盘大/小带occludens-1（PDZ）域的人蛋白酪氨酸磷酸酶1 E蛋白（hPTP 1 E）（PDZ 2）。发现大多数突变对肽配体结合没有显着的能量贡献。三个突变体，结合表现出显着的变化，也表现出上下文依赖的动态效应。与野生型PDZ 2相比，在部分暴露位点（H71 Y）和掩埋核心位置（I35 V）的突变在侧链2 H-基动力学中具有有限的响应。相比之下，在第二个核心位置（I20 F）的变化，以前已被证明是一个充满活力和动态的网络的一部分，导致侧链动力学的广泛变化。这种反应使人想起先前在肽配体结合时所看到的反应。这些结果揭示了PDZ 2动态网络的性质，并表明在PDZ 2中的位置20充当“枢纽”，其在能量和动态上对于在整个PDZ域中传输动态变化至关重要。(c)2006爱思唯尔有限公司保留所有权利。
A number of computational and experimental studies have identified intramolecular communication "pathways" or "networks" important for transmitting allostery. Here, we have used mutagenesis and NMR relaxation methods to investigate the scope and nature of the communication networks found in the second post-synaptic density-95/discs large/zonula occludens-1 (PDZ) domain of the human protein tyrosine phosphatase 1E protein (hPTP1E) (PDZ2). It was found that most mutations do not have a significant energetic contribution to peptide ligand binding. Three mutants that showed significant changes in binding also displayed context-dependent dynamic effects. Both a mutation at a partially exposed site (H71Y) and a buried core position (I35V) had a limited response in side-chain 2 H-based dynamics when compared to wild-type PDZ2. In contrast, a change at a second core position (I20F) that had previously been shown to be part of an energetic and dynamic network, resulted in extensive changes in side-chain dynamics. This response is reminiscent to that seen previously upon peptide ligand binding. These results shed light on the nature of the PDZ2 dynamic network and suggest that position 20 in PDZ2 acts as a "hub" that is energetically and dynamically critical for transmitting changes in dynamics throughout the PDZ domain. (c) 2006 Elsevier Ltd. All rights reserved.