The Contribution of Missense Mutations in Core and Rim Residues of Protein-Protein Interfaces to Human Disease.
The Contribution of Missense Mutations in Core and Rim Residues of Protein-Protein Interfaces to Human Disease.
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DOI：
10.1016/j.jmb.2015.07.004
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发表时间：
2015-08-28
影响因子：
5.6
通讯作者：
Sternberg MJ
中科院分区：
文献类型：
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作者：
David A;Sternberg MJ
蛋白质-蛋白质相互作用位点（称为界面）的错义突变是导致人类疾病的重要因素。界面是不均匀的表面区域，以两个主要区域“核心”和“边缘”为特征，这两个区域在进化保守性和物理化学性质方面有所不同。此外，在界面内，只有一小部分残基（“热点”）对于蛋白质-蛋白质复合物的结合自由能至关重要。我们对人类单氨基酸变异 (SAV) 进行了大规模结构分析，并证明致病突变优先位于界面核心内，而不是边缘 (p < 0.01)。相反，界面边缘的多态性显着丰富，类似于剩余的非相互作用表面。与非热点相比，能量热点往往富含致病突变（p = 0.05），无论它们出现在核心还是边缘残基中。对于单个氨基酸，多态性或致病突变的取代频率与其他氨基酸不同，并且与其结构位置相关，以及 SAV 引入的物理化学变化的类型。总之，本研究证明了致病 SAV 的不同分布和特性以及不同结构区域内的多态性，以及与蛋白质-蛋白质界面中氨基酸的能量贡献相关，从而强调了结构系统生物学方法对于预测 SAV 效应的重要性。蛋白质-蛋白质相互作用是所有生物过程的基础。蛋白质界面内有害和非 SAV 的分布尚不清楚。有害SAV在不同界面结构区域内的分布不同。 SAV 的分布因界面残基能量贡献而异。蛋白质复合物的结构分析增强了对有害 SAV 的理解。
Missense mutations at protein–protein interaction sites, called interfaces, are important contributors to human disease. Interfaces are non-uniform surface areas characterized by two main regions, “core” and “rim”, which differ in terms of evolutionary conservation and physicochemical properties. Moreover, within interfaces, only a small subset of residues (“hot spots”) is crucial for the binding free energy of the protein–protein complex. We performed a large-scale structural analysis of human single amino acid variations (SAVs) and demonstrated that disease-causing mutations are preferentially located within the interface core, as opposed to the rim (p < 0.01). In contrast, the interface rim is significantly enriched in polymorphisms, similar to the remaining non-interacting surface. Energetic hot spots tend to be enriched in disease-causing mutations compared to non-hot spots (p = 0.05), regardless of their occurrence in core or rim residues. For individual amino acids, the frequency of substitution into a polymorphism or disease-causing mutation differed to other amino acids and was related to its structural location, as was the type of physicochemical change introduced by the SAV. In conclusion, this study demonstrated the different distribution and properties of disease-causing SAVs and polymorphisms within different structural regions and in relation to the energetic contribution of amino acid in protein–protein interfaces, thus highlighting the importance of a structural system biology approach for predicting the effect of SAVs. Protein–protein interactions are fundamental in all biological processes. The distribution of deleterious and non-SAVs within protein interfaces is unknown. The distribution of deleterious SAVs differs within different interface structural regions. The distribution of SAVs differs in relation to interface residues energetic contribution. Structural analysis of protein complexes enhances the understanding of deleterious SAVs.