Uncovering new signaling proteins and potential drug targets through the interactome analysis of Mycobacterium tuberculosis.
Uncovering new signaling proteins and potential drug targets through the interactome analysis of Mycobacterium tuberculosis.
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通过结核分枝杆菌的相互作用组分析发现新的信号蛋白和潜在的药物靶点
DOI：
10.1186/1471-2164-10-118
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发表时间：
2009-03-19
期刊：
影响因子：
4.4
通讯作者：
He ZG
中科院分区：
文献类型：
--
作者：
Cui T;Zhang L;Wang X;He ZG
背景
病原体相互作用组的分析是剖析潜在的信号转导和毒力途径的有力方法。它还为探索新的药物靶点提供了机会。
结果
在这项研究中，蛋白质-蛋白质相互作用（PPI）网络的结核分枝杆菌H37 Rv构建使用同源蛋白质图谱的方法，这表明分子伴侣，核糖体蛋白和ABC转运蛋白是高度互连的蛋白质。对该网络的进一步分析揭示了假设蛋白质的功能以及潜在的信号通路。一个假设的蛋白质，Rv 2752 c，这是连接到一个金属阳离子转运ATP酶，其特征在于作为一个金属-β-内酰胺酶，通过结构域分析结合体外活性实验。第二个假设的蛋白质，Rv 1354 c，和一个未知的蛋白激酶，PknK，与PPI网络中的一组类似的内膜相关ABC转运蛋白相互作用。Rv 1354与这些蛋白质的相互作用也通过进一步的细菌双杂交分析证实。根据蛋白质结构域的结构，独特的M。首次提出结核Rv 1354 c基因负责该细菌中第二信使分子cyclic-di-GMP的周转。还在硅中进行了Rv 1354 c的进一步的基于结构的抑制剂筛选。
结论
我们构建了一个完整的M.结核杆菌的基因组由738个蛋白质和5639个相互作用对组成。我们的分析揭示了假设蛋白质的功能以及潜在的信号通路。ABC转运蛋白、PknK和Rv 1354 c可能构成了一条潜在的膜相关信号通路，协同响应环境胁迫。结核因此，该研究为探索新的信号蛋白、毒力通路和药物靶点提供了有价值的线索。
Background
Analysis of the pathogen interactome is a powerful approach for dissecting potential signal transduction and virulence pathways. It also offers opportunities for exploring new drug targets.
Results
In this study, a protein-protein interaction (PPI) network of Mycobacterium tuberculosis H37Rv was constructed using a homogenous protein mapping method, which has shown molecular chaperones, ribosomal proteins and ABC transporters to be highly interconnected proteins. A further analysis of this network unraveled the function of hypothetical proteins as well as a potential signaling pathway. A hypothetical protein, Rv2752c, which was linked to a metal cation-transporting ATPase, was characterized as a metal-beta-lactamase, through domain analysis in combination with an in vitro activity experiment. A second hypothetical protein, Rv1354c, and an unknown protein kinase, PknK, interacted with a similar group of inner membrane-associated ABC transporters in the PPI network. The interactions of Rv1354 with these proteins were also confirmed by a further bacterial two-hybrid analysis. According to protein domain structures, the unique M. tuberculosis Rv1354c gene was proposed, for the first time, to be responsible for the turnover of cyclic-di-GMP, a second messenger molecule in this bacterium. A further structure-based inhibitors screening for Rv1354c was also performed in silicon.
Conclusion
We constructed a comprehensive protein-protein interaction network for M. tuberculosis consisting of 738 proteins and 5639 interaction pairs. Our analysis unraveled the function of hypothetical proteins as well as a potential signaling pathway. The group of ABC transporters, PknK, and Rv1354c were proposed to constitute a potential membrane-associated signaling pathway that cooperatively responds to environmental stresses in M. tuberculosis. The study therefore provides valuable clues in exploring new signaling proteins, virulence pathways, and drug targets.
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