Cancer missense mutations alter binding properties of proteins and their interaction networks.
Cancer missense mutations alter binding properties of proteins and their interaction networks.
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DOI：
10.1371/journal.pone.0066273
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Panchenko AR
中科院分区：
文献类型：
--
作者：
Nishi H;Tyagi M;Teng S;Shoemaker BA;Hashimoto K;Alexov E;Wuchty S;Panchenko AR
许多研究表明，错义突变可能在肿瘤发生中起重要作用。然而，癌症突变可能影响生物分子相互作用的程度仍不清楚。在这里，我们绘制了人类蛋白质相互作用组上的胶质母细胞瘤错义突变，模拟了受影响的蛋白质复合物的结构，并破译了突变对蛋白质-蛋白质，蛋白质-核酸和蛋白质-离子结合界面的影响。虽然一些错义突变过度稳定蛋白质复合物，但我们发现突变的总体效果是不稳定的，主要影响结合能的静电分量。我们还表明，突变的接口导致更剧烈的变化的氨基酸的物理化学性质比突变发生在接口之外。对界面上胶质母细胞瘤突变的分析使我们能够对癌症相关的相互作用进行分层，识别潜在的驱动基因，并提出24种额外的癌症生物标志物，包括那些特异于神经系统功能的生物标志物。这种分析还提供了对突变的表型结果的分子机制的洞察，包括对复合物稳定性、活性、结合和周转率的影响。作为突变蛋白和基因网络分析的结果，我们观察到，与蛋白质上其他地方的突变相互作用或未受影响的相互作用相比，蛋白质与映射在界面上的突变的相互作用具有更高的瓶颈特性。这些观察结果表明，具有直接影响蛋白质结合特性的突变的基因优选地位于中心网络位置，并且可能影响信号转导网络中的关键节点和边缘。
Many studies have shown that missense mutations might play an important role in carcinogenesis. However, the extent to which cancer mutations might affect biomolecular interactions remains unclear. Here, we map glioblastoma missense mutations on the human protein interactome, model the structures of affected protein complexes and decipher the effect of mutations on protein-protein, protein-nucleic acid and protein-ion binding interfaces. Although some missense mutations over-stabilize protein complexes, we found that the overall effect of mutations is destabilizing, mostly affecting the electrostatic component of binding energy. We also showed that mutations on interfaces resulted in more drastic changes of amino acid physico-chemical properties than mutations occurring outside the interfaces. Analysis of glioblastoma mutations on interfaces allowed us to stratify cancer-related interactions, identify potential driver genes, and propose two dozen additional cancer biomarkers, including those specific to functions of the nervous system. Such an analysis also offered insight into the molecular mechanism of the phenotypic outcomes of mutations, including effects on complex stability, activity, binding and turnover rate. As a result of mutated protein and gene network analysis, we observed that interactions of proteins with mutations mapped on interfaces had higher bottleneck properties compared to interactions with mutations elsewhere on the protein or unaffected interactions. Such observations suggest that genes with mutations directly affecting protein binding properties are preferably located in central network positions and may influence critical nodes and edges in signal transduction networks.
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影响因子：
3.7
作者：
Cerami E;Demir E;Schultz N;Taylor BS;Sander C
通讯作者：
Sander C
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
5.6
作者：
Guerois, R;Nielsen, JE;Serrano, L
通讯作者：
Serrano, L
影响因子：
5.6
作者：
Hosur R;Xu J;Bienkowska J;Berger B
通讯作者：
Berger B
影响因子：
14.9
作者：
Dinkel H;Chica C;Via A;Gould CM;Jensen LJ;Gibson TJ;Diella F
通讯作者：
Diella F